rs1555148035

chr12-32877908-CGCCT-CAGC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001005242.3(PKP2):c.968_971delinsGCT(p.Gln323ArgfsTer29) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32877909-GCCT-AGC is Pathogenic according to our data. Variant chr12-32877909-GCCT-AGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.968_971delinsGCT	p.Gln323ArgfsTer29	frameshift_variant	3/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.968_971delinsGCT	p.Gln323ArgfsTer29	frameshift_variant	3/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This variant replaces 4 nucleotides in exon 3 of the PKP2 gene with 3 novel nucleotides, causing a frameshift and premature truncation stop signal. This variant is expected to result in an absent or nonfunctional protein product. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 09, 2017	The p.Gln323fs variant in PKP2 has not been previously reported in individuals w ith arrhythmogenic right ventricular cardiomyopathy (ARVC) or in large populatio n studies. This variant is predicted to cause a frameshift, which alters the pro tein?s amino acid sequence beginning at position 323 and leads to a premature te rmination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function is an established mechan ism of disease for the PKP2 gene. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Gln323fs variant is l ikely pathogenic. -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 04, 2022

This sequence change creates a premature translational stop signal (p.Gln323Argfs*29) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with PKP2-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 31, 2023

This variant replaces 4 nucleotides in exon 3 of the PKP2 gene with 3 novel nucleotides, causing a frameshift and premature truncation stop signal. This variant is expected to result in an absent or nonfunctional protein product. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555148035; hg19: chr12-33030843;