rs1555149975

Positions:

• chr12-32896663-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001005242.3(PKP2):​c.68del​(p.Gly23AspfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G23G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.0430

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 230 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32896663-TC-T is Pathogenic according to our data. Variant chr12-32896663-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 464431.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.68del	p.Gly23AspfsTer16	frameshift_variant	1/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.68del	p.Gly23AspfsTer16	frameshift_variant	1/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 11, 2019

This sequence change deletes 1 nucleotide from exon 1 of the PKP2 mRNA (c.68delG), causing a frameshift at codon 23. This creates a premature translational stop signal (p.Gly23Aspfs*16) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Apr 11, 2017

Given that loss of function variation is a known mechanism of disease in PKP2 and its absence from large population databases, we consider this variant disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This particular variant appears novel. It has not been reported in the literature and is not present in ClinVar. However, loss of function variation is a known mechanism of disease in PKP2. At least two dozen splice variants in this gene have been reported in association with ARVC (see http://www.arvcdatabase.info/). The majority of the disease-associated variants in PKP2 are splicing variants, frameshift, nonsense, or in-frame deletions. In one study 66 of 149 unrelated ARVC patients had such a variant (Cox et al 2011). In contrast, these variants are rare in the general population (Kapplinger et al 2011, NHLBI ESP). A study by Amr et al (2016) also supports the assumption that the PKP2 gene is intolerant to loss of function variation, reporting loss of function variants enriched in cases vs controls (OR: 114). There is no variation at codon 23 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 31x. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1555149975; hg19: chr12-33049597;