rs794729137

Positions:

chr12-32841072-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001005242.3(PKP2):c.1511del(p.Gly504ValfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.16

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-32841072-AC-A is Pathogenic according to our data. Variant chr12-32841072-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 202035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32841072-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3 linkuse as main transcript	c.1511del	p.Gly504ValfsTer15	frameshift_variant	6/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9 linkuse as main transcript	c.1511del	p.Gly504ValfsTer15	frameshift_variant	6/13	1	NM_001005242.3	P1	Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change creates a premature translational stop signal (p.Gly548Valfs*15) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 20031617, 20400443, 24070718, 24704780, 24967631). This variant is also known as c.1642delG. ClinVar contains an entry for this variant (Variation ID: 202035). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2019	The PKP2 c.1643delG; p.Gly548fs variant (rs794729137), also published as 1642delG, is reported in the literature in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Alcalde 2014, Dalal 2006, den Haan 2009, Gerull 2004). This variant occurred in all affected members of a kindred with ARVC, though it was also found in several asymptomatic individuals, suggesting incomplete penetrance (Dalal 2006). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Alcalde M et al. Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy. PLoS One. 2014 Jun 26;9(6):e100560. Dalal D et al. Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2006 Oct 3;48(7):1416-24. den Haan AD et al. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. Gerull B et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004 Nov;36(11):1162-4. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 08, 2018	The c.1643delG (p.Gly548Valfs15) frameshift variant in the PKP2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) [PMID 15489853, 17010805, 19358943, 20152563, 20400443, 21723241, 23810883, 24967631].Therefore, this c.1643delG (p.Gly548Valfs15) variant in the PKP2 gene is classified as pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This variant deletes 1 nucleotide in exon 7 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten unrelated individuals affected with arrhythmogenic cardiomyopathy (15489853, 20152563, 20400443, 23810883, 24704780, 24967631, 28588093, 29940860, 30790397, 31702781). It has been shown that this variant segregates with disease in at least two of these families (PMID: 17010805, 24704780). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 05, 2018	The p.Gly548ValfsX15 variant in PKP2 has been reported in at least 7 individuals with either possible or definitive diagnosis of ARVC and segregated with diseas e in 1 affected relative (Gerull 2004, Dalal 2006, Perrin 2013, Fressart 2010, D alal 2006, LMM data). This variant is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino ac id sequence beginning at position 548 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. Heterozygous loss of function of the PKP2 gene is an est ablished disease mechanism in ARVC. In summary, this variant is pathogenic in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15489853, 20857253, 28097316, 20400443, 23810883, 21723241, 20031617, 19358943, 20152563, 24070718, 17010805, 26850880, 29606362, 24704780, 24967631, 30790397, 32155531, 30535908, 31702781, 30161220, 32102357, 31447099, 31402444, 32372669, 31386562, 29940860, 35819174, 34120153, 34134068, 23810894, 28588093) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 08, 2020	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. (PMID: 17010805, 20031617, 20152563, 20400443, 24967631, 29940860, 30790397).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 03, 2023

This variant deletes 1 nucleotide in exon 7 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten unrelated individuals affected with arrhythmogenic cardiomyopathy (15489853, 20152563, 20400443, 23810883, 24704780, 24967631, 28588093, 29940860, 30790397, 31702781). It has been shown that this variant segregates with disease in at least two of these families (PMID: 17010805, 24704780). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2018

The c.1643delG pathogenic mutation, located in coding exon 7 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 1643, causing a translational frameshift with a predicted alternate stop codon (p.G548Vfs*15). This alteration has been described in multiple patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat Genet. 2004;36(11):1162-4; Xu T et al. J Am Coll Cardiol. 2010;55(6):587-97; Fressart V et al. Europace. 2010;12(6):861-8; te Riele AS et al. J Am Coll Cardiol. 2013;62(19):1761-9; Perrin MJ et al. J Am Coll Cardiol. 2013;62(19):1772-9; Alcalde M et al. PLoS ONE. 2014;9(6):e100560). In one study, this alteration was described to co-segregate with ARVC in two siblings; however, additional relatives with this alteration in the same family exhibited either absent or limited clinical phenotype suggesting reduced penetrance (Dalal D et al. J Am Coll Cardiol. 2006;48(7):1416-24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Familial isolated arrhythmogenic right ventricular dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 08, 2020

Variant summary: PKP2 c.1643delG (p.Gly548ValfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251310 control chromosomes (gnomAD). c.1643delG has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example: Hermida_2019, Hoorntje_2018, Segura-Rodriguez_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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