rs1114167429
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS2PP2PS4_SupportingPM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.166G>C (p.Ala56Pro) variant in PPP1CB is a missense variant predicted to cause substitution of alanine by proline at amino acid 56. This variant is absent from gnomAD v4 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.463, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:27264673). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:27264673). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_P, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA346581171/MONDO:0021060/128
Frequency
Consequence
NM_002709.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome-like disorder with loose anagen hair 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 31, 2017 | - - |
RASopathy Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Sep 17, 2024 | The c.166G>C (p.Ala56Pro) variant in PPP1CB is a missense variant predicted to cause substitution of alanine by proline at amino acid 56. This variant is absent from gnomAD v4 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.463, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:27264673). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID: 27264673). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_P, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at