12-32843259-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004572.4(PKP2):​c.1433C>G​(p.Ala478Gly) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PKP2
NM_004572.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.385
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.083450854).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKP2NM_001005242.3 linkc.1379-2054C>G intron_variant Intron 5 of 12 ENST00000340811.9 NP_001005242.2 Q99959-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKP2ENST00000340811.9 linkc.1379-2054C>G intron_variant Intron 5 of 12 1 NM_001005242.3 ENSP00000342800.5 Q99959-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
15
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
May 04, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces alanine with glycine at codon 478 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
1.7
DANN
Benign
0.34
DEOGEN2
Benign
0.14
T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.0027
N
LIST_S2
Benign
0.32
T
M_CAP
Benign
0.0020
T
MetaRNN
Benign
0.083
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.16
N
REVEL
Benign
0.040
Sift
Benign
0.33
T
Sift4G
Benign
0.69
T
Polyphen
0.0
B
Vest4
0.26
MutPred
0.35
Gain of disorder (P = 0.0671);
MVP
0.31
MPC
0.16
ClinPred
0.043
T
GERP RS
-1.0
Varity_R
0.096
gMVP
0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-32996193; API