Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NEB Version 1.0.0

Description : The Congenital Myopathies VCEP aims to (1) define criteria for the specific classification of variants related to congenital myopathies based on the ACMG standards and guidelines for variant interpretation and classification, and (2) review the majority of reported variants that have been associated with these disorders to provide expert-approved classification for their clinical significance, starting with 5 genes that have been described as having Definitive evidence for a causal role in disease: ACTA1, NEB, MTM1, DNM2, RYR1.

Version : 1.0.0

Congenital Myopathies VCEP

Released

8/7/2024

13:31:09

Rules for NEB

Gene: NEB (HGNC:7720) HGNC Name: nebulin Transcripts: NM_001164507.1 NM_001164508.2 Disease: nemaline myopathy (MONDO:0018958) Mode of Inheritance: Autosomal recessive inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). Use caution interpreting LOF variants at the extreme 3’ end of a gene. Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. Use caution in the presence of multiple transcripts. Specified critical regions in NEB that should also receive PVS1 are listed below and in the PVS1 flowchart: In-frame deletions due to the repetitive nature of NEB, particularly in exon 55, are deleterious and pathogenic (Anderson 2004 PMID:15221447, Lehtokari 2009 PMID:19232495). Exons 161-183 (Pelin 1999 PMID:10051637). Modification Type: Gene-specific Strong In-frame deletions due to the repetitive nature of NEB, particularly in exon 55, are deleterious and pathogenic (Anderson 2004 PMID:15221447, Lehtokari 2009 PMID:19232495). The majority of NEB exons are in frame (exons 3-180, 182); thus, skipping of in-frame exons should be scored at PVS1_Strong. Modification Type: Gene-specific Moderate See PVS1 flowchart Modification Type: Gene-specific Supporting See PVS1 flowchart Modification Type: Gene-specific Instructions: See PVS1 flowchart Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong Strong De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength. Modification Type: Disease-specific Moderate The two assays from PS3_Supporting may be stacked to reach a Moderate Strength Modification Type: Gene-specific Supporting Two specific assays are currently suggested to be applied at Supporting: Thin filament structure: An abnormal readout consists of a significant difference in intensity reflections of X-ray diffraction patterns generated by muscle fibers from patient biopsies compared to WT. In vitro motility: An abnormal readout consists of a significant difference in speed of single fibers derived from patient muscle compared to WT. If not listed above, it is acceptable to use PS3_Supporting for other functional analyses if The assay has been validated by a known pathogenic and benign variant AND There is plausible reason that the function the assay is testing relates to the phenotype AND The assay conditions are likely to mimic the physiological environment. Modification Type: Gene-specific Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. NEB is associated with Autosomal Recessive disease; PS4 can only be used for case-control studies and not proband counting. Please use PM3 for individual case observations. Modification Type: Disease-specific,Gene-specific Moderate NEB is associated with Autosomal Recessive disease; PS4 can only be used for case-control studies and not proband counting. Please use PM3 for individual case observations. Modification Type: Gene-specific Supporting NEB is associated with Autosomal Recessive disease; PS4 can only be used for case-control studies and not proband counting. Please use PM3 for individual case observations. Modification Type: Gene-specific Instructions: NEB is associated with Autosomal Recessive disease; PS4 can only be used for case-control studies and not proband counting. Please use PM3 for individual case observations. Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: There are no defined hotspots or critical functional domains in NEB at this time.
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is ≤ 0.0000559. 1 allele is allowed. Modification Type: Disease-specific,Gene-specific Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong 4.0 points per the PM3 chart Modification Type: Disease-specific Strong 2.0 points per the PM3 chart Modification Type: Disease-specific Moderate For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. 1.0 points per the PM3 chart Modification Type: Disease-specific Supporting 0.5 points per the PM3 chart Modification Type: Disease-specific Instructions: Please use the SVI-recommended PM3 chart to count observations. Points for each proband should be summed to get to a final PM3 strength. In order to count to count case counts for your variant of interest, it should be rare enough to not meet BS1. PM3 Chart Not Applicable
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong In-frame deletions due to the repetitive nature of NEB, particularly in exon 55, are deleterious and pathogenic (Anderson 2004 PMID:15221447, Lehtokari 2009 PMID:19232495). Modification Type: Gene-specific Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Modification Type: No change Supporting No change - use as originally described Modification Type: No change Instructions: Either PVS1_Strong or PM4_Strong, but not both, should be used for in-frame deletions in NEB. Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong No change - use as originally described Modification Type: No change Moderate Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Modification Type: No change Supporting No change - use as originally described Modification Type: No change Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong No change - use as originally described Modification Type: No change Moderate Assumed de novo, but without confirmation of paternity and maternity. Modification Type: No change Supporting No change - use as originally described Modification Type: No change Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong See segregation chart Modification Type: General recommendation Moderate See segregation chart Modification Type: General recommendation Supporting Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. See segregation chart Modification Type: General recommendation Instructions: The segregation chart (adopted from Oza et al 2018 PMID:30311386) should be used to determine the strength level of the total number of affected and unaffected segregations. In order to count unaffected segregations, the unaffected individuals can be heterozygous carriers or WT, but should have the same risk of inheriting the variant as the affected individuals (e.g. siblings in the same generation). Segregation chart Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: NEB is not a gene that is constrained for missense variation. Hence PP2 is not applicable.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5 Modification Type: General recommendation Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Supporting PP4 is met with the presence of any of these features Presence on Muscle Biopsy of: Nemaline rods Shorter thin filaments Functional assays performed upon patient muscle biopsy indicate: Significantly altered Calcium sensitivity Significantly altered muscle mechanics (altered force-sarcomere length or reduced contractile strength and force generation) Modification Type: Disease-specific,Gene-specific Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is ≥0.00559. All populations used should have at least 2000 alleles and >1 observation. The Ashkenazi Jewish, European Finnish, and Other populations in gnomAD will not be used for BA1 application. BA1 exclusion variants (well-known pathogenic variants that are above the specified BA1 threshold) are as follows: Exon 55 deletion common in the AJ population (NM_001271208.2:c.7431+1919_7536+374del) NM_001271208.2:c.19097G>T (p.Ser6366Ile) NM_001271208.2:c.22249A>C (p.Thr7417Pro) Modification Type: Disease-specific,Gene-specific Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is ≥0.000237 in continental populations. All populations used should have at least 2000 alleles and >1 observation. Modification Type: Disease-specific,Gene-specific Moderate Supporting Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Moderate The two assays from BS3_Supporting may be stacked to reach a Moderate Strength Modification Type: Gene-specific Supporting Two specific assays are currently suggested to be applied at Supporting: Thin filament structure: A normal readout consists of no significant difference in intensity reflections of X-ray diffraction patterns generated by muscle fibers from patient biopsies compared to WT. In vitro motility: A normal readout consists of no a significant difference in speed of single fibers derived from patient muscle compared to WT. Modification Type: Gene-specific Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Both missense and truncating variants in NEB are disease-causing.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong No change - use as originally described Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Modification Type: No change Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: There are no regions in NEB where BP3 would apply.
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI. Modification Type: General recommendation Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong No change - use as originally described Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting Variant found in a case with an alternate molecular basis for disease. Modification Type: No change Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Modification Type: General recommendation Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PS3_Very Strong, PS4_Very Strong, PM3_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong, PP4_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PS3_Very Strong, PS4_Very Strong, PM3_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PS3_Very Strong, PS4_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND 1 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PS3_Very Strong, PS4_Very Strong, PM3_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong, PP4_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong, PP4_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong, PP4_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong, PP4_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong, PP4_Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Benign

≥ 2 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong, BP7_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong, BP7_Strong) AND 1 Supporting (BS2_Supporting, BS3_Supporting, BS4_Supporting, BP2, BP4, BP5, BP7)

≥ 2 Supporting (BS2_Supporting, BS3_Supporting, BS4_Supporting, BP2, BP4, BP5, BP7)

Files & Images

Segregation chart:

PVS1 decision tree for NEB:

NEB approved functional assays:

References

1. Anderson SL Ekstein J et al. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet (2004) 115 (3) p. 185-90. 10.1007/s00439-004-1140-8 15221447

2. Lehtokari VL Greenleaf RS et al. The exon 55 deletion in the nebulin gene--one single founder mutation with world-wide occurrence. Neuromuscul Disord (2009) 19 (3) p. 179-81. 10.1016/j.nmd.2008.12.001 19232495

3. Pelin K Hilpelä P et al. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A (1999) 96 (5) p. 2305-10. 10.1073/pnas.96.5.2305 10051637

4. Oza AM DiStefano MT et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat (2018) 39 (11) p. 1593-1613. 10.1002/humu.23630 30311386