rs149930872
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The ENST00000070846.11(PKP2):c.1468C>T(p.Arg490Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 711,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R490Q) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000070846.11 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1379-2019C>T | intron_variant | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1379-2019C>T | intron_variant | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000507 AC: 77AN: 151844Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000422 AC: 97AN: 230084Hom.: 0 AF XY: 0.000438 AC XY: 55AN XY: 125432
GnomAD4 exome AF: 0.000420 AC: 235AN: 559126Hom.: 1 Cov.: 8 AF XY: 0.000460 AC XY: 139AN XY: 302148
GnomAD4 genome ? AF: 0.000507 AC: 77AN: 151962Hom.: 0 Cov.: 32 AF XY: 0.000485 AC XY: 36AN XY: 74274
ClinVar
Submissions by phenotype
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2016 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 18, 2022 | Variant summary: PKP2 c.1468C>T (p.Arg490Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools (Alamut) predict no significant impact on normal splicing, which was confirmed by Gandjbakhch_2011 using transcriptional analysis in heart tissue. The variant allele was found at a frequency of 0.00042 in 231024 control chromosomes, predominantly at a frequency of 0.00093 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1468C>T has been reported in the literature in individuals affected with arrhythmogenic right ventricular cardiomyopathy, sudden unexplained death and cardiac disease (Gandjbakhch_2011, Sanchez_2016, Iglesia_2021). Additionally, one publication reported three siblings, including two reported as affected/possibly affected ARVC and one reported as unaffected, and suggested this variant is not fully penetrant or does not segregate with disease. Moreover, another variant (DSP p.Glu2343Lys) was found in all three family members and may explain the phenotype in these patients (Gandjbakhch_2011). Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign/benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 04, 2013 | Arg490Trp in exon 6 of PKP2: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , orangutan, rhesus macaque, baboon, and marmoset have a tryptophan (Trp) at thi s position despite high nearby amino acid conservation. Addtionally, functional studies have shown that this variant does not impact splicing (Gandjbankhch 201 1). It has also been identified in 0.15% (7/4402) of African American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs149930872). Arg490Trp in exon 6 of PKP2 (rs149930872; allele frequency = 0 .15%, 7/4402) ** - |
Cardiomyopathy Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Oct 02, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 16, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 18, 2018 | - - |
Arrhythmogenic right ventricular dysplasia 9 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PKP2: BP4 - |
Becker muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
Dilated cardiomyopathy 3B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
Duchenne muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2019 | This alteration is classified as likely 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