rs397516996
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001005242.3(PKP2):βc.14delβ(p.Gly5AlafsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,316,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. G5G) has been classified as Likely benign.
Frequency
Consequence
NM_001005242.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.14del | p.Gly5AlafsTer34 | frameshift_variant | 1/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.14del | p.Gly5AlafsTer34 | frameshift_variant | 1/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000228 AC: 3AN: 1316948Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 645872
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 20, 2012 | The Gly5Alafs variant in PKP2 has not been reported in the literature nor previo usly identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 5 and lead to a prematu re termination codon 34 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. Heterozygous loss-of-function varian ts in the PKP2 gene are common in patients with ARVC. In summary, this variant i s likely to be pathogenic, though additional studies are required to fully estab lish its clinical significance. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2019 | Reported in ClinVar (ClinVar Variant ID# 45027; Landrum et al., 2016) and segregated with disease in multiple family members as reported by another clinical laboratory (ClinVar SCV000845655.1; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28588093, 28506445, 25820315, 29759408, 30765282, 31386562, 31402444) - |
Arrhythmogenic ventricular cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub | Sep 12, 2017 | This variant causes a frameshift, and is predicted to lead to the introduction of a premature termination codon, generating a truncated or absent protein. Loss of function variants in PKP2 are known to be pathogenic. This variant has not been detected in approximately 60,000 individuals in control populations (ExAC database), and has been reported in other individuals with ARVC (ClinVar variation ID 45027; Groeneweg et al. Circ Cardiovasc Genet. 2015;8:437-46). It has been shown to segregate with disease in mutiple family members in our lab. - |
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2018 | Variant summary: PKP2 c.14delG (p.Gly5AlafsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Arg79X and p.Gln133X). The variant was absent in 30714 control chromosomes. c.14delG has been reported in the literature in one individual affected with Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Another clinical diagnostic laboratory has submitted assessment for this variant to ClinVar before 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Therefore, at-least 3 index cases with this variant have been identified. Based on the evidence outlined above, the variant was classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at