12-32796167-G-T

Variant names:

• chr12-32796167-G-T
• rs139734328
• NM_001005242.3:c.2299C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001005242.3(PKP2):​c.2299C>A​(p.Arg767Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000855 in 1,614,042 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts 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. R767H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (7 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19
• Conservation: PhyloP100: 3.69
• Publications: 22 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020314664).
• BP6: Variant 12-32796167-G-T is Benign according to our data. Variant chr12-32796167-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45068.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000749 (114/152206) while in subpopulation AMR AF = 0.000851 (13/15282). AF 95% confidence interval is 0.000664. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 114 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005242.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	NM_001005242.3	MANE Select	c.2299C>A	p.Arg767Ser	missense	Exon 11 of 13	NP_001005242.2
	PKP2	NM_004572.4		c.2431C>A	p.Arg811Ser	missense	Exon 12 of 14	NP_004563.2
	PKP2	NM_001407156.1		c.2134C>A	p.Arg712Ser	missense	Exon 10 of 12	NP_001394085.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP2	ENST00000340811.9	TSL:1 MANE Select	c.2299C>A	p.Arg767Ser	missense	Exon 11 of 13	ENSP00000342800.5
	PKP2	ENST00000070846.11	TSL:1	c.2431C>A	p.Arg811Ser	missense	Exon 12 of 14	ENSP00000070846.6
	PKP2	ENST00000549461.3	TSL:2	c.442C>A	p.Arg148Ser	missense	Exon 3 of 5	ENSP00000519092.1

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152088 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000907 AC: 228 AN: 251482 AF XY: 0.00101

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000866 AC: 1266 AN: 1461836 Hom.: 7 Cov.: 34 AF XY: 0.000920 AC XY: 669 AN XY: 727226

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00880 AC: 230 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.000730 AC: 812 AN: 1111962

Other (OTH) AF: 0.00136 AC: 82 AN: 60394

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152206 Hom.: 1 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74402

African (AFR) AF: 0.000120 AC: 5 AN: 41526

American (AMR) AF: 0.000851 AC: 13 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:19

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:1 Benign:5

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 02, 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.

Jun 09, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:5

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25637381, 20400443, 20857253, 23299917, 23810883, 24832006, 20829228, 23861362, 25351510, 26743238, 26656175, 26332594, 28341588, 29582136, 30731207, 31402444)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKP2: BP4, BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:3

Jun 12, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKP2 c.2431C>A (p.Arg811Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 253076 control chromosomes (gnomAD, Fressart_2010, Klauke_2010, Tan_2010), including 1 homozygote in the gnomAD database. The observed variant frequency is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00065), suggesting that the variant is benign. c.2431C>A has been reported in the literature in individuals affected with ARVD and other cardiological phenotypes (Fressart_2010, Klauke_2010, Tan_2010, Bottillo_2016, Proost_2017, Chua_2018, Sahlin_2019), however without strong evidence for pathogenicity (i.e. lack of co-segregation data), these reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. In addition, co-occurrences with other pathogenic variants have been reported in the literature (MYBPC3 c.3192dup (p.Lys1065fsX12), Bottillo_2016; DSG2 c.137G>A, p.Arg46Gln, Fressart_2010), providing supporting evidence for a benign role. 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: 24832006, 23299917, 26656175, 29582136, 20400443, 20829228, 23810883, 28341588, 30615648, 20857253). Eleven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, seven as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign.

Aug 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4

Cardiomyopathy Benign:2

Apr 10, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arrhythmogenic right ventricular cardiomyopathy Benign:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Sep 26, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome Uncertain:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: BS1, PP3

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

PKP2-related disorder Benign:1

May 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Cardiovascular phenotype Benign:1

Oct 30, 2018

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.024	D
Polyphen		0.27	B
Vest4		0.81
MVP		0.73
MPC		0.54
ClinPred		0.088	T
GERP RS		5.1
Varity_R		0.34
gMVP		0.59
Mutation Taster		=78/22	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: rs139734328; hg19: chr12-32949101; COSMIC: COSV50756535; COSMIC: COSV50756535;