chr12-32822594-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_001005242.3(PKP2):c.1712C>T(p.Ser571Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S571T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001005242.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1712C>T | p.Ser571Phe | missense_variant | 8/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1712C>T | p.Ser571Phe | missense_variant | 8/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727206
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 27, 2022 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 615 of the PKP2 protein (p.Ser615Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 15489853, 23671136; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406555). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PKP2 function (PMID: 22781308). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at