rs1046116

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001005242.3(PKP2):c.1097T>C(p.Leu366Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,613,432 control chromosomes in the GnomAD database, including 38,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3000 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35883 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 1.97

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008521527).

BP6

Variant 12-32869000-A-G is Benign according to our data. Variant chr12-32869000-A-G is described in ClinVar as [Benign]. Clinvar id is 45006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32869000-A-G is described in Lovd as [Benign]. Variant chr12-32869000-A-G is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.1097T>C	p.Leu366Pro	missense_variant	Exon 4 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.1097T>C	p.Leu366Pro	missense_variant	Exon 4 of 13	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.198

AC:

30093

AN:

152040

Hom.:

2999

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.180

Gnomad EAS

AF:

0.0327

Gnomad SAS

AF:

0.155

Gnomad FIN

AF:

0.198

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.224

Gnomad OTH

AF:

0.194

GnomAD3 exomes

AF:

0.180

AC:

45239

AN:

251308

Hom.:

4492

AF XY:

0.182

AC XY:

24718

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.199

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.0294

Gnomad SAS exome

AF:

0.163

Gnomad FIN exome

AF:

0.194

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.191

GnomAD4 exome

AF:

0.216

AC:

316176

AN:

1461272

Hom.:

35883

Cov.:

AF XY:

0.215

AC XY:

156088

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.201

Gnomad4 AMR exome

AF:

0.133

Gnomad4 ASJ exome

AF:

0.172

Gnomad4 EAS exome

AF:

0.0277

Gnomad4 SAS exome

AF:

0.165

Gnomad4 FIN exome

AF:

0.193

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.208

GnomAD4 genome

AF:

0.198

AC:

30112

AN:

152160

Hom.:

3000

Cov.:

AF XY:

0.195

AC XY:

14492

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.195

Gnomad4 AMR

AF:

0.166

Gnomad4 ASJ

AF:

0.180

Gnomad4 EAS

AF:

0.0328

Gnomad4 SAS

AF:

0.155

Gnomad4 FIN

AF:

0.198

Gnomad4 NFE

AF:

0.224

Gnomad4 OTH

AF:

0.193

Alfa

AF:

0.212

Hom.:

8095

Bravo

AF:

0.196

TwinsUK

AF:

0.230

AC:

852

ALSPAC

AF:

0.226

AC:

870

ESP6500AA

AF:

0.200

AC:

883

ESP6500EA

AF:

0.230

AC:

1979

ExAC

AF:

0.180

AC:

21856

Asia WGS

AF:

0.111

AC:

384

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Benign:6

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:5

Jul 04, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:3

Apr 24, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:2

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27153395, 19863551, 20864495, 25445213) -

Cardiovascular phenotype

Benign:1

Dec 08, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

0.060

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.4

DANN

Benign

0.24

DEOGEN2

Benign

0.087

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.18

T;T

MetaRNN

Benign

0.0085

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.72

N;N

REVEL

Benign

0.13

Sift

Benign

0.41

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0

B;B

Vest4

0.10

MPC

0.25

ClinPred

0.0021

GERP RS

4.2

Varity_R

0.18

gMVP

0.33

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