rs533659697

Positions:

chr12-32822510-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting

The NM_001005242.3(PKP2):c.1796A>G(p.Lys599Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,140 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K599E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.22

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 Likely_benign. Variant got -4 ACMG points.

PM1

In a repeat ARM 4 (size 45) in uniprot entity PKP2_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001005242.3

BP4

Computational evidence support a benign effect (MetaRNN=0.059651107).

BP6

Variant 12-32822510-T-C is Benign according to our data. Variant chr12-32822510-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464416.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3 linkuse as main transcript	c.1796A>G	p.Lys599Arg	missense_variant	8/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9 linkuse as main transcript	c.1796A>G	p.Lys599Arg	missense_variant	8/13	1	NM_001005242.3	P1	Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251342

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 643 of the PKP2 protein (p.Lys643Arg). This variant is present in population databases (rs533659697, 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: 464416). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 20, 2017

The p.Lys643Arg variant (rs533659697) has not been reported in the medical literature and is not listed in gene-specific variant databases. It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in East Asian populations of 0.03% (identified in 6 out of 17,242 chromosomes). The lysine at codon 643 is moderately conserved considering 8 species (Alamut software v2.9), and computational analyses suggest this variant does not have a significant effect on PKP2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Lys643Arg variant cannot be determined with certainty. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 15, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 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

0.075

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

0.81

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.066

Sift

Benign

0.22

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0020

B;B

Vest4

0.19

MutPred

0.24

.;Loss of ubiquitination at K643 (P = 0.027);

MVP

0.63

MPC

0.13

ClinPred

0.027

GERP RS

2.6

Varity_R

0.066

gMVP

0.41

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

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