rs397517017

Positions:

• chr12-32821382-G-A

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.1987C>T​(p.Gln663Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.56

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 12-32821382-G-A is Pathogenic according to our data. Variant chr12-32821382-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32821382-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1987C>T	p.Gln663Ter	stop_gained	9/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1987C>T	p.Gln663Ter	stop_gained	9/13	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:2

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

Aug 22, 2012

The Gln707X variant in PKP2 has been identified in 1 Italian individual with ARV C and was absent from at least 1400 control chromosomes (Basso 2006, Bauce 2010, Xu 2010). However, this variant did not segregate with disease in 1 affected re lative and this proband carried 2 other variants (1 in PKP2 and 1 in DSP; Bauce 2010, Xu 2010). The Gln707X variant has not been identified in large and broad E uropean American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). In addition, this nonsense variant l eads to a premature termination codon at position 707, which is predicted to lea d to a truncated or absent protein. Heterozygous loss of function of the PKP2 ge ne is an established disease mechanism in patients with ARVC, though reduced pen etrance and variable expressivity are common. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 28, 2021

Reported in association with ARVC (Bauce et al., 2010; Ohno et al., 2013; Walsh et al., 2017; Smith et al., 2020); however some patients harbored additional cardiogenetic variants and this variant did not segregate with disease in one relative (Bauce et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 45059; ClinVar); This variant is associated with the following publications: (PMID: 25525159, 31918855, 16774985, 32372669, 31402444, 27532257, 20152563, 23514727, 26582918, 20129281) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.85
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs397517017; hg19: chr12-32974316;