rs1425855043
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001005242.3(PKP2):c.775G>T(p.Glu259Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,876 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: 0.0000014 ( 0 hom. )
Consequence
PKP2
NM_001005242.3 stop_gained
NM_001005242.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.12
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]
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ACMG classification
Classification made for transcript
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 12-32878105-C-A is Pathogenic according to our data. Variant chr12-32878105-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 464432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32878105-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.775G>T | p.Glu259Ter | stop_gained | 3/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.775G>T | p.Glu259Ter | stop_gained | 3/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727244
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | This sequence change creates a premature translational stop signal (p.Glu259*) 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 premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). ClinVar contains an entry for this variant (Variation ID: 464432). For these reasons, this variant has been classified as Pathogenic. - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 13, 2020 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at