rs199583774

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001005242.3(PKP2):โ€‹c.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

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15

Conservation

PhyloP100: 1.44
Variant links:
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]

Genome browser will be placed here

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
PKP2NM_001005242.3 linkuse as main transcriptc.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
PKP2ENST00000340811.9 linkuse as main transcriptc.1951C>T p.Arg651Cys missense_variant 9/131 NM_001005242.3 ENSP00000342800 P1Q99959-2

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000220
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251388
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000139
AC:
203
AN:
1461858
Hom.:
0
Cov.:
32
AF XY:
0.000147
AC XY:
107
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000268
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000243
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000130
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.000181
ExAC
AF:
0.000148
AC:
18
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000296

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 23, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 providedclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJan 27, 2016- -
not specified Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 07, 2021Variant 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 submitterclinical testingAl Jalila Childrenโ€™s Genomics Center, Al Jalila Childrens Speciality HospitalDec 23, 2019- -
Uncertain significance, no assertion criteria providedclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 30, 2008- -
not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicApr 20, 2023- -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 27, 2023Reported 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 submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioNov 14, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 08, 2023This 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 submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 11, 2024This 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 providedclinical testingBlueprint GeneticsSep 29, 2014- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 14, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.62
.;D
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Uncertain
0.70
D;D
MetaSVM
Uncertain
0.032
D
MutationAssessor
Uncertain
2.5
.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-5.0
D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.63
MVP
0.84
MPC
0.78
ClinPred
0.49
T
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.23
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199583774; hg19: chr12-32974352; API