rs199583774
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_001005242.3(PKP2):โc.1951C>Tโ(p.Arg651Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (โ โ ).
Frequency
Genomes: ๐ 0.00015 ( 0 hom., cov: 32)
Exomes ๐: 0.00014 ( 0 hom. )
Consequence
PKP2
NM_001005242.3 missense
NM_001005242.3 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 1.44
Genes affected
PKP2 (HGNC:9024): (plakophilin 2) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000139 (203/1461858) while in subpopulation MID AF= 0.00121 (7/5768). AF 95% confidence interval is 0.000569. There are 0 homozygotes in gnomad4_exome. There are 107 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1951C>T | p.Arg651Cys | missense_variant | 9/13 | ENST00000340811.9 | NP_001005242.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1951C>T | p.Arg651Cys | missense_variant | 9/13 | 1 | NM_001005242.3 | ENSP00000342800 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152056Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 33AN: 251388Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135874
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GnomAD4 exome AF: 0.000139 AC: 203AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.000147 AC XY: 107AN XY: 727224
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74424
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 695 of the PKP2 protein (p.Arg695Cys). This variant is present in population databases (rs199583774, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PKP2-related conditions (PMID: 26220970, 26743238, 28074886, 28750076, 36178741). This variant is also known as c.C1951T (p.R651C). ClinVar contains an entry for this variant (Variation ID: 45056). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 23, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jan 27, 2016 | - - |
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2021 | Variant summary: PKP2 c.2083C>T (p.Arg695Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251388 control chromosomes. This frequency is not higher than the maximum expected for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVC) (0.00065), allowing no conclusion about variant significance. However, in certain subpopulations the variant was found at a higher frequency, e.g. in Southern Europeans control individuals the variant occurs with a frequency of 0.00087, suggesting that the variant maybe a benign polymorphism. The variant, c.2083C>T, has been reported in the literature in individuals affected with various cardiac phenotypes, including ARVC (Adler_2016), Brugada syndrome (Di Resta_2015), dilated cardiomyopathy (Forleo_2017) and sudden infant death syndrome (SIDS) (Neubauer_2017), however it was also found in healthy controls (Kapplinger_2011, Narang_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Childrenโs Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 23, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 30, 2008 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2023 | Reported in one family with ARVC (Adler et al., 2016), in one patient with sudden infant death (SIDS) (Neubauer et al., 2017), one patient with DCM (Forleo et al., 2017), and two patients referred for Brugada syndrome (Di Resta et al., 2015); however, additional clinical information was not provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21636032, 28074886, 26220970, 32906206, 28750076, 26743238, 34033898, 35932045) - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 14, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 08, 2023 | This missense variant replaces arginine with cysteine at codon 695 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238), one individual affected with dilated cardiomyopathy (PMID: 28750076), and one individual affected with idiopathic ventricular tachycardia (PMID: 33552729). This variant has also been identified in 36/282782 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces arginine with cysteine at codon 695 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238), one individual affected with dilated cardiomyopathy (PMID: 28750076), and one individual affected with idiopathic ventricular tachycardia (PMID: 33552729). This variant has also been identified in 36/282782 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Sep 29, 2014 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2022 | The c.2083C>T (p.R695C) alteration is located in exon 10 (coding exon 10) of the PKP2 gene. This alteration results from a C to T substitution at nucleotide position 2083, causing the arginine (R) at amino acid position 695 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.78
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at