12-32878954-C-T

Variant names:

• chr12-32878954-C-T
• rs149542398
• NM_001005242.3:c.302G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

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. 15/22 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. R101L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: -0.196
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 45076.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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	c.302G>A	p.Arg101His	missense_variant	Exon 2 of 13	ENST00000340811.9	NP_001005242.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152152 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251412 AF XY: 0.000132

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 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.: 1 Cov.: 28 AF XY: 0.000505 AC XY: 364 AN XY: 721290

African (AFR) AF: 0.0000603 AC: 2 AN: 33174

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.000709 AC: 781 AN: 1101148

Other (OTH) AF: 0.000251 AC: 15 AN: 59770

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74340

African (AFR) AF: 0.000121 AC: 5 AN: 41420

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000417 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:3 Benign: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. -

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. -

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. -

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 -

not provided Uncertain:2 Benign: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:1 Benign: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 Benign:1

Jun 09, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		-0.20
PrimateAI	Benign	0.29	T
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	T
GERP RS		0.71
Varity_R		0.035
gMVP		0.27
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs149542398; hg19: chr12-33031888; COSMIC: COSV50748148;