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.
For general information about the ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding content correction or adding a new criteria specification refer to the Help page.
Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know by contacting us via email.
Criteria & Strength Specifications
|
||||
---|---|---|---|---|
PVS1 | ||||
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:
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 | ||||
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 | ||||
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 | ||||
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:
If not listed above, it is acceptable to use PS3_Supporting for other functional analyses if
Modification Type:
Gene-specific
Not Applicable
|
||||
PS4 | ||||
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 | ||||
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 | ||||
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 | ||||
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. Not Applicable
|
||||
PM4 | ||||
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 | ||||
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 | ||||
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 | ||||
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). Not Applicable
|
||||
PP2 | ||||
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 | ||||
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 | ||||
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:
Functional assays performed upon patient muscle biopsy indicate:
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 | ||||
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 | ||||
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 | ||||
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 | ||||
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:
Modification Type:
Gene-specific
Not Applicable
|
||||
BS4 | ||||
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 | ||||
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 | ||||
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 | ||||
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 | ||||
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 | ||||
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 | ||||
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
|
One Baylor Plaza, MS:BCM225 Suite 400D, Houston, TX, 77030
Questions or comments?