chr12-32877952-C-T

Position:

chr12-32877952-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001005242.3(PKP2):c.928G>A(p.Val310Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,614,028 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.05

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]

PKP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054295987).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000158 (24/152230) while in subpopulation AMR AF= 0.00105 (16/15282). AF 95% confidence interval is 0.000656. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3 linkuse as main transcript	c.928G>A	p.Val310Met	missense_variant	3/13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9 linkuse as main transcript	c.928G>A	p.Val310Met	missense_variant	3/13	1	NM_001005242.3	ENSP00000342800	P1	Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

251022

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000800

AC:

117

AN:

1461798

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000872

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000158

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 310 of the PKP2 protein (p.Val310Met). This variant is present in population databases (rs768396351, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201962). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces valine with methionine at codon 310 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 performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 24/282426 chromosomes 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 09, 2023

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2024

Has not been previously published as pathogenic or benign in association with a PKP2-related disorder to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21636032) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

CADD

Benign

7.7

DANN

Benign

0.80

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.070

N;N

REVEL

Benign

0.19

Sift

Benign

0.27

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0040

B;B

Vest4

0.10

MutPred

0.29

Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);

MVP

0.65

MPC

0.16

ClinPred

0.029

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.35

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