Criteria Specification Registry

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Criteria Specification

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PPP1CB Version 1.0.0

Description : These are the ACMG/AMP variant classification specifications developed by the RASopathy VCEP for PPP1CB.

Version : 1.0.0

RASopathy VCEP

Released

8/3/2024

01:05:38

Rules for PPP1CB

Gene: PPP1CB (HGNC:9282) HGNC Name: protein phosphatase 1 catalytic subunit beta Transcripts: NM_002709.3 Disease: RASopathy (MONDO:0021060) Mode of Inheritance: Autosomal dominant 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 Strong Moderate Supporting Not Applicable Comments: 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 in PPP1CB regardless of nucleotide change. Modification Type: Analogous Gene Moderate Supporting Instructions: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Not Applicable Comments: Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below: * Group 1: HRAS, NRAS, KRAS * Group 2: MAP2K1, MAP2K2 * Group 3: SOS1, SOS2
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 4 Points. Modification Type: Strength Strong 2 Points. Modification Type: None Moderate 1 Point. Modification Type: Strength Supporting Instructions: Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)). Not Applicable Comments: PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.
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 Moderate Supporting Instructions: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials. Not Applicable Comments: Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval. PS3 is not applicable for PPP1CB at this time.
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 ≥5 points. Modification Type: Disease-specific Moderate ≥3 points. Modification Type: Strength Supporting ≥1 points. Modification Type: Strength Instructions: Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)). Not Applicable Comments: PS4: ≥5 independent occurrences PS4_Moderate: ≥3 independent occurrences PS4_Supporting: ≥1 independent occurrences
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 Instructions: Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Not Applicable Comments: Not applicable for PPP1CB.
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 The variant must be absent from controls (gnomAD). Modification Type: Strength Instructions: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Not Applicable Comments: The variant must be completely absent from all population databases.
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 Strong Moderate Supporting Not Applicable Comments: 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 Moderate No known repetitive areas in gene. Use as described. Modification Type: General recommendation Supporting Instructions: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. 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 ≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands. Modification Type: Strength Moderate 1 [likely] pathogenic residue change at the same codon observed in ≥5 probands. Modification Type: Disease-specific Supporting Instructions: Applicable for observed analogous residue positions in PPP1CB. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5_Strong is applied to avoid overweighting. Not Applicable Comments: Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below: Group 1: HRAS, NRAS, KRAS Group 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2 This rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.
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 2 Points. Modification Type: Strength Moderate 1 Point. Modification Type: None Supporting 0.5 Points. Modification Type: Strength Instructions: Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)). Not Applicable Comments: PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events. PS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.
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 ≥7 informative meioses. Modification Type: Strength Moderate ≥5 informative meioses. Modification Type: Strength Supporting ≥3 informative meioses. Modification Type: Disease-specific Instructions: Segregation in more than one family is recommended. Not Applicable Comments: PP1_Moderate: ≥5 informative meioses PP1_Strong: ≥7 informative meioses
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 Missense z score is <3.09 in gnomAD. Modification Type: Gene-specific Instructions: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Not Applicable Comments: Not applicable because missense z score is <3.09 in gnomAD.
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 For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism. Modification Type: Disease-specific Instructions: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). 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 Not Applicable Comments: Not applicable, see PS4.
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 GnomAD filtering allele frequency ≥0.05%. Modification Type: Disease-specific Very Strong Strong Moderate Supporting Instructions: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Not Applicable Comments: An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.
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 GnomAD filtering allele frequency ≥0.025%. Modification Type: Disease-specific Moderate Supporting Instructions: Allele frequency is greater than expected for disorder. Not Applicable Comments: An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.
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 -4 Points. Modification Type: Strength Moderate Supporting -1 Point. Modification Type: Strength Instructions: Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations. Not Applicable Comments: Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.
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 Supporting Instructions: Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Not Applicable Comments: Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.
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 Requires only one informative meiosis. Modification Type: General recommendation Moderate Supporting Instructions: Lack of segregation in affected members of a family. Not Applicable Comments: Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.
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 This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants. Modification Type: Disease-specific Instructions: Missense variant in a gene for which primarily truncating variants are known to cause disease. Not Applicable Comments: This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.
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 ≥ (-4) Points. Modification Type: Strength Moderate ≥ (-2) Points. Modification Type: Strength Supporting ≥ (-1) Point. Modification Type: None Instructions: Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy. 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: No known benign repetitive areas in RASopathy genes.
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 For missense variants: REVEL ≤0.3. Modification Type: Disease-specific Instructions: For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism. 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 ≥ (-4) Points. Modification Type: Strength Moderate ≥ (-2) Points. Modification Type: Strength Supporting ≥ (-1) Point. Modification Type: None Instructions: Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing). 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 (silent) 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. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4. Modification Type: General recommendation Instructions: 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. Not Applicable Comments: This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.

Rules for Combining Criteria

Pathogenic

1 Very Strong (PS2_Very Strong) AND ≥ 1 Strong (PS1, PS2, PS4, PM5_Strong, PM6_Strong, PP1_Strong)

1 Very Strong (PS2_Very Strong) AND ≥ 2 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate)

1 Very Strong (PS2_Very Strong) AND 1 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate) AND 1 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM6_Supporting, PP1, PP2, PP3)

1 Very Strong (PS2_Very Strong) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM6_Supporting, PP1, PP2, PP3)

≥ 2 Strong (PS1, PS2, PS4, PM5_Strong, PM6_Strong, PP1_Strong)

1 Strong (PS1, PS2, PS4, PM5_Strong, PM6_Strong, PP1_Strong) AND ≥ 3 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PS1, PS2, PS4, PM5_Strong, PM6_Strong, PP1_Strong) AND 2 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM6_Supporting, PP1, PP2, PP3)

1 Strong (PS1, PS2, PS4, PM5_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM6_Supporting, PP1, PP2, PP3)

Likely Pathogenic

1 Very Strong (PS2_Very Strong) AND 1 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PS1, PS2, PS4, PM5_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PS1, PS2, PS4, PM5_Strong, PM6_Strong, PP1_Strong) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM6_Supporting, PP1, PP2, PP3)

≥ 3 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate)

2 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM6_Supporting, PP1, PP2, PP3)

1 Moderate (PS2_Moderate, PS4_Moderate, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PS3_Supporting, PS4_Supporting, PM2_Supporting, PM6_Supporting, PP1, PP2, PP3)

Benign

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

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong) AND 1 Supporting (BS2_Supporting, BP1, BP2, BP4, BP5, BP7)

≥ 2 Supporting (BS2_Supporting, BP1, BP2, BP4, BP5, BP7)

1 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong)

1 Strong (BS1)

Files & Images

Approved Functional Studies: This documentation specifies which assays can be used in the application of PS3/BS3 and at what strength.

References

1. https://clinicalgenome.org/site/assets/files/3461/svi_proposal_for_de_novo_criteria_v1_1.pdf