rs147240502
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001005242.3(PKP2):c.1460T>G(p.Ile487Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,612,890 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001005242.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00397 AC: 604AN: 152126Hom.: 5 Cov.: 32
GnomAD3 exomes AF: 0.00480 AC: 1207AN: 251382Hom.: 4 AF XY: 0.00482 AC XY: 655AN XY: 135842
GnomAD4 exome AF: 0.00411 AC: 6000AN: 1460646Hom.: 28 Cov.: 30 AF XY: 0.00406 AC XY: 2948AN XY: 726754
GnomAD4 genome AF: 0.00397 AC: 604AN: 152244Hom.: 5 Cov.: 32 AF XY: 0.00476 AC XY: 354AN XY: 74432
ClinVar
Submissions by phenotype
not specified Benign:3
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
p.Ile531Ser in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 2.6% (170/6614) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs147240502). -
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Arrhythmogenic right ventricular dysplasia 9 Benign:3
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided Benign:3
Variant summary: The PKP2 c.1592T>G (p.Ile531Ser) variant causes a missense change with 3/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a damaging outcome for this variant. This variant was found in 867/136406 control chromosomes (2 homozygotes) at a frequency of 0.006356, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0004301), suggesting this variant is likely a benign polymorphism. In addition, multiple publications report the variant to co-occur with other potentially pathogenic variants. In the few small pedigrees published, the variant did not segregate within families, leading authors to conclude that this variant could be modulating the effect of another variant or this variant could have low penetrance. Furthermore, functional studies support the variant to have comparable to wild-type function. In addition, multiple reputable clinical diagnostic laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -
PKP2: BP4, BS1, BS2 -
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Cardiomyopathy Benign:2
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Family history of cardiomyopathy Benign:1
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Arrhythmogenic right ventricular cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at