Variant 11-396893-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_007183.4(PKP3):c.392G>A(p.Arg131Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000761 in 1,445,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

PKP3
NM_007183.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

PKP3 (HGNC:9025): (plakophilin 3) 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 protein may act in cellular desmosome-dependent adhesion and signaling pathways. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

PKP3 links:

PKP3 (HGNC:):

PKP3 links:

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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=0.09137091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP3	NM_007183.4 linkuse as main transcript	c.392G>A	p.Arg131Gln	missense_variant	3/13	ENST00000331563.7	NP_009114.1	Q9Y446-1
PKP3	NM_001303029.2 linkuse as main transcript	c.437G>A	p.Arg146Gln	missense_variant	4/14		NP_001289958.1	Q9Y446-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP3	ENST00000331563.7 linkuse as main transcript	c.392G>A	p.Arg131Gln	missense_variant	3/13	1	NM_007183.4	ENSP00000331678.2		Q9Y446-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000929

AC:

AN:

215222

Hom.:

AF XY:

0.00

AC XY:

AN XY:

118972

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000306

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000350

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000761

AC:

AN:

1445282

Hom.:

Cov.:

AF XY:

0.00000696

AC XY:

AN XY:

718402

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000542

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000167

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.392G>A (p.R131Q) alteration is located in exon 3 (coding exon 3) of the PKP3 gene. This alteration results from a G to A substitution at nucleotide position 392, causing the arginine (R) at amino acid position 131 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.022

.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.091

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

.;N;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.36

.;N;N

REVEL

Benign

0.13

Sift

Benign

0.64

.;T;T

Sift4G

Uncertain

0.047

D;T;T

Polyphen

0.026

.;B;.

Vest4

0.15

MutPred

0.40

.;Loss of MoRF binding (P = 0.0304);.;

MVP

0.49

MPC

0.079

ClinPred

0.044

GERP RS

1.6

Varity_R

0.033

gMVP

0.29

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over