rs397516996

Positions:

• chr12-32896717-GC-G

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.14del​(p.Gly5AlafsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,316,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G5G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.60

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 231 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32896717-GC-G is Pathogenic according to our data. Variant chr12-32896717-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45027.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.14del	p.Gly5AlafsTer34	frameshift_variant	1/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.14del	p.Gly5AlafsTer34	frameshift_variant	1/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000228 AC: 3 AN: 1316948 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 645872

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: 0.00000287

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 20, 2012

The Gly5Alafs variant in PKP2 has not been reported in the literature nor previo usly identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 5 and lead to a prematu re termination codon 34 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. Heterozygous loss-of-function varian ts in the PKP2 gene are common in patients with ARVC. In summary, this variant i s likely to be pathogenic, though additional studies are required to fully estab lish its clinical significance. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2019

Reported in ClinVar (ClinVar Variant ID# 45027; Landrum et al., 2016) and segregated with disease in multiple family members as reported by another clinical laboratory (ClinVar SCV000845655.1; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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: 28588093, 28506445, 25820315, 29759408, 30765282, 31386562, 31402444) -

Arrhythmogenic ventricular cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub

Sep 12, 2017

This variant causes a frameshift, and is predicted to lead to the introduction of a premature termination codon, generating a truncated or absent protein. Loss of function variants in PKP2 are known to be pathogenic. This variant has not been detected in approximately 60,000 individuals in control populations (ExAC database), and has been reported in other individuals with ARVC (ClinVar variation ID 45027; Groeneweg et al. Circ Cardiovasc Genet. 2015;8:437-46). It has been shown to segregate with disease in mutiple family members in our lab. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 05, 2018

Variant summary: PKP2 c.14delG (p.Gly5AlafsX34) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Arg79X and p.Gln133X). The variant was absent in 30714 control chromosomes. c.14delG has been reported in the literature in one individual affected with Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Another clinical diagnostic laboratory has submitted assessment for this variant to ClinVar before 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Therefore, at-least 3 index cases with this variant have been identified. Based on the evidence outlined above, the variant was classified as Pathogenic. -

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: rs397516996; hg19: chr12-33049651;