12-32878954-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001005242.3(PKP2):c.302G>A(p.Arg101His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,600,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: -0.196

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]

PKP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.068145454).

BP6

Variant 12-32878954-C-T is Benign according to our data. Variant chr12-32878954-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45076.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=8}. Variant chr12-32878954-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000302 (46/152152) while in subpopulation NFE AF= 0.000588 (40/68026). AF 95% confidence interval is 0.000444. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.302G>A	p.Arg101His	missense_variant	Exon 2 of 13	ENST00000340811.9	NP_001005242.2	Q99959-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9 link	c.302G>A	p.Arg101His	missense_variant	Exon 2 of 13	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251412

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000553

AC:

801

AN:

1447952

Hom.:

Cov.:

AF XY:

0.000505

AC XY:

364

AN XY:

721290

show subpopulations

Gnomad4 AFR exome

AF:

0.0000603

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000709

Gnomad4 OTH exome

AF:

0.000251

GnomAD4 genome

AF:

0.000302

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000377

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Uncertain:3Benign:1

Nov 21, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (ARVD9; MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17010805, PMID: 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 17010805, PMID: 23183494). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (46 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes each). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as likely benign in ClinVar and as VUS in multiple individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy and Brugada syndrome (ClinVar, PMID: 20400443, 23396983, 24503780, 26230511), and also reported in an unaffected control individual (PMID: 23861362). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 101 of the PKP2 protein (p.Arg101His). This variant is present in population databases (rs149542398, gnomAD 0.03%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy, Brugada syndrome and dilated cardiomyopathy (PMID: 20400443, 23861362, 24503780, 25351510, 26230511, 33029862). ClinVar contains an entry for this variant (Variation ID: 45076). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Jan 20, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg101His variant (rs149542398) has been observed in several cohorts of cardiomyopathy patients (selected references: Allegue 2015, Fressart 2010, Pugh 2014) and one control cohort (Ng 2013); however, specific clinical information and segregated data were not provided. This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.034% (identified in 43 out of 126,664 chromosomes). It is also listed in the ClinVar database (Variation ID: 45076). The arginine at codon 101 is weakly conserved considering 8 species (Alamut software v2.9), and computational analyses suggest this does not have a significant effect on PKP2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Arg101His variant cannot be determined with certainty. -

not provided

Uncertain:2Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 02, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4 -

Feb 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with various clinical phenotypes including DCM, ARVC, HCM, and Brugada syndrome (Fressart et al., 2010; Lopes et al., 2013; Pugh et al., 2014; Allegue et al., 2015); Observed in one individual from a cohort not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death that underwent exome sequencing (Ng et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 45076; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30821013, 27085656, 25351510, 23396983, 23861362, 24503780, 20400443, 26230511) -

not specified

Uncertain:1Benign:1

Jan 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg101His in exon 2 of PKP2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, the seal and 3 bat species have a histidine (His) at this position despite h igh nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been iden tified in 13/66714 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org/; dbSNP rs149542398). -

Sep 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKP2 c.302G>A (p.Arg101His) 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. The variant allele was found at a frequency of 0.00016 in 282808 control chromosomes (gnomAD), predominantly at a frequency of 0.00031 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00016 vs 0.00065), allowing no conclusion about variant significance. c.302G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g Fressart_2010), Hypertrophic Cardiomyopathy (e.g. Lopes_2013), Dilated Cardiomyopathy (e.g. Pugh_2014) and Brugada Syndrome (e.g. Allegue_2015). 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. The following publications have been ascertained in the context of this evaluation (PMID: 26230511, 30821013, 20400443, 23396983, 24503780). Ten ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, and five as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy

Benign:2

Jan 08, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Conduction disorder of the heart

Uncertain:1

Apr 14, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R101H variant (also known as c.302G>A), located in coding exon 2 of the PKP2 gene, results from a G to A substitution at nucleotide position 302. The arginine at codon 101 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in individuals with Brugada syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy, although many also carried variants in other cardiac-related genes (Pugh TJ et al. Genet Med. 2014;16(8):601-8; Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Allegue C et al. PLoS ONE. 2015;10(7):e0133037). In addition, this variant was reported in an individual with arrhythmogenic right ventricular cardiomyopathy who was also homozygous for a DSG2 pathogenic mutation (Fressart V et al. Europace. 2010;12(6):861-8). This variant has also been reported as a secondary cardiac variant of unknown significance in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in one species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.2

L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.19

Sift

Uncertain

0.027

D;D

Sift4G

Benign

0.16

T;T

Polyphen

0.025

B;B

Vest4

0.21

MVP

0.72

MPC

0.20

ClinPred

0.044

GERP RS

0.71

Varity_R

0.035

gMVP

0.27

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over