rs397517015

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1PM2PP5_ModerateBS2_Supporting

The NM_001005242.3(PKP2):​c.1867G>T​(p.Glu623*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000342 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.69
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 12-32821502-C-A is Pathogenic according to our data. Variant chr12-32821502-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 45054.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-32821502-C-A is described in Lovd as [Pathogenic].
BS2
High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKP2NM_001005242.3 linkuse as main transcriptc.1867G>T p.Glu623* stop_gained 9/13 ENST00000340811.9 NP_001005242.2 Q99959-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKP2ENST00000340811.9 linkuse as main transcriptc.1867G>T p.Glu623* stop_gained 9/131 NM_001005242.3 ENSP00000342800.5 Q99959-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251356
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461856
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
show subpopulations
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 06, 2010The Glu667X variant has not been reported in the literature. It leads to a prema ture stop at codon 667, which is predicted to lead to a truncated or absent prot ein. The severity nature of the change combined with the fact that pathogenic no nsense variants are very common in the PKP2 gene makes it highly likely that the Glu667X variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.84
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397517015; hg19: chr12-32974436; API