2-158533267-T-G

Position:

• chr2-158533267-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003628.6(PKP4):​c.83T>G​(p.Met28Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKP4 NM_003628.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

Genes affected

PKP4 (HGNC:9026): (plakophilin 4) Armadillo-like proteins are characterized by a series of armadillo repeats, first defined in the Drosophila 'armadillo' gene product, that are typically 42 to 45 amino acids in length. These proteins can be divided into subfamilies based on their number of repeats, their overall sequence similarity, and the dispersion of the repeats throughout their sequences. Members of the p120(ctn)/plakophilin subfamily of Armadillo-like proteins, including CTNND1, CTNND2, PKP1, PKP2, PKP4, and ARVCF. PKP4 may be a component of desmosomal plaque and other adhesion plaques and is thought to be involved in regulating junctional plaque organization and cadherin function. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

PKP4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP4	NM_003628.6	c.83T>G	p.Met28Arg	missense_variant	2/22	ENST00000389759.8	NP_003619.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP4	ENST00000389759.8	c.83T>G	p.Met28Arg	missense_variant	2/22	1	NM_003628.6	ENSP00000374409.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2024

The p.M28R variant (also known as c.83T>G), located in coding exon 1 of the PKP4 gene, results from a T to G substitution at nucleotide position 83. The methionine at codon 28 is replaced by arginine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T;.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.6	.;L;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	.;N;N;.
REVEL	Uncertain	0.39
Sift	Benign	0.065	.;T;T;.
Sift4G	Benign	0.11	T;T;T;D
Polyphen		0.89, 0.84	.;P;P;.
Vest4		0.72
MutPred		0.14		Loss of phosphorylation at T33 (P = 0.1283);Loss of phosphorylation at T33 (P = 0.1283);Loss of phosphorylation at T33 (P = 0.1283);Loss of phosphorylation at T33 (P = 0.1283);
MVP		0.83
MPC		0.56
ClinPred		0.82	D
GERP RS		6.2
Varity_R		0.48
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-159389779;