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GeneBe

rs146102241

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001005242.3(PKP2):c.1627G>C(p.Val543Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V543I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PKP2
NM_001005242.3 missense

Scores

2
9
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.10
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-32824092-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PKP2NM_001005242.3 linkuse as main transcriptc.1627G>C p.Val543Leu missense_variant 7/13 ENST00000340811.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PKP2ENST00000340811.9 linkuse as main transcriptc.1627G>C p.Val543Leu missense_variant 7/131 NM_001005242.3 P1Q99959-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.84
T;T
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Benign
-0.69
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-0.79
N;N
REVEL
Uncertain
0.30
Sift
Benign
0.20
T;T
Sift4G
Uncertain
0.037
D;D
Polyphen
1.0
D;D
Vest4
0.68
MutPred
0.55
.;Gain of catalytic residue at V587 (P = 0.0476);
MVP
0.73
MPC
0.66
ClinPred
0.93
D
GERP RS
5.3
Varity_R
0.35
gMVP
0.73

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

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

Other links and lift over

dbSNP: rs146102241; hg19: chr12-32977026; API