rs794729124

Positions:

• chr12-32868964-TGTATGAAA-T

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.1125_1132del​(p.Phe376AlafsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,502 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PKP2 NM_001005242.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.89

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 12-32868964-TGTATGAAA-T is Pathogenic according to our data. Variant chr12-32868964-TGTATGAAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 202016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32868964-TGTATGAAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1125_1132del	p.Phe376AlafsTer8	frameshift_variant	4/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1125_1132del	p.Phe376AlafsTer8	frameshift_variant	4/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461502 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change creates a premature translational stop signal (p.Phe376Alafs*8) 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 variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 202016). For these reasons, this variant has been classified as Pathogenic. -

PKP2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2023

The PKP2 c.1125_1132del8 variant is predicted to result in a frameshift and premature protein termination (p.Phe376Alafs*8). This variant has been reported in an individual with arrhythmogenic right ventricular dysplasia (Table S1A - Walsh et al. 2017. PubMed ID: 27532257). In ClinVar, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/202016). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in PKP2 are expected to be pathogenic, and therefore we interpret c.1125_1132del (p.Phe376Alafs*8) as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2012

Although the c.1125_1132del TTTCATAC variant in the PKP2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Phenylalanine 376, changing it to a Alanine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Phe376AlafsX8. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variant in the PKP2 gene have been reported in association with ARVC. In summary, c.1125_1132del TTTCATAC in the PKP2 gene is interpreted as a pathogenic variant. -

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: rs794729124; hg19: chr12-33021898;