rs727504786

chr12-32792669-GT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001005242.3(PKP2):c.2419del(p.Thr807ArgfsTer80) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T807T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.193

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0378 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32792669-GT-G is Pathogenic according to our data. Variant chr12-32792669-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179315.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.2419del	p.Thr807ArgfsTer80	frameshift_variant	12/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.2419del	p.Thr807ArgfsTer80	frameshift_variant	12/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

Apr 08, 2015

The p.Thr851fsExtX50 variant in PKP2 has not been previously reported in any oth er families with cardiomyopathy or in large population studies. This variant is predicted to cause a frameshift at amino acid 851 which alters the terminal 30 a mino acids and the stop codon such that an additional 50 amino acids are generat ed before introducing a new stop codon. Heterozygous loss of PKP2 function is an established disease mechanism for ARVC; however it is unclear how the p.Thr851f sExtX50 variant would impact the protein function. Of note, 4 other variants hav ing a similar impact to the protein (p.Ser837fsExtX50, p.Leu847fsExtX50, p.Glu85 2fsExtX50, p.Lys859fsExtX50) have been described in >15 individuals with ARVC (G erull 2004, Antoniades 2006, Dalal 2006, Asimaki 2009, Dalal 2009, Fressart 2010 , Den Haan 2009, Watkins 2009, Qiu 2009, Xu 2010, Barahona-Dussault 2010, Tan, 2 010, Cox 2011, Baskin 2013, Alcalde 2014), suggesting that PKP2 protein extensio n variants are disease-causing. In summary, although additional studies are requ ired to fully establish its clinical significance, the p.Thr851fsExtX50 variant is likely 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: rs727504786; hg19: chr12-32945603;