ENST00000070846.11:c.1462G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000070846.11(PKP2):c.1462G>A(p.Gly488Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 790,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. G488D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

PKP2
ENST00000070846.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.454

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 9
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PKP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018732578).

BP6

Variant 12-32843230-C-T is Benign according to our data. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142. Variant chr12-32843230-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 229142.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00021 (32/152284) while in subpopulation AFR AF = 0.000698 (29/41558). AF 95% confidence interval is 0.000498. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.1379-2025G>A		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
PKP2	ENST00000340811.9 link	c.1379-2025G>A		intron_variant	Intron 5 of 12	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000635

AC:

AN:

236120

AF XY:

0.0000233

show subpopulations

Gnomad AFR exome

AF:

0.000763

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000219

AC:

AN:

638166

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

339462

show subpopulations

African (AFR)

AF:

0.000593

AC:

AN:

15178

American (AMR)

AF:

0.0000822

AC:

AN:

36504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13382

East Asian (EAS)

AF:

0.00

AC:

AN:

14228

South Asian (SAS)

AF:

0.00

AC:

AN:

71930

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

436358

Other (OTH)

AF:

0.0000790

AC:

AN:

25304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000210

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41558

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Dec 17, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gly488Ser variant in PKP2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (7/7726) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs537458442). Computational prediction tools and conservation analysis are limited or unavailable for this variant. In summary, the clinical significance of the p.Gly488Ser variant is uncertain. -

Arrhythmogenic right ventricular dysplasia 9

Uncertain:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 488 of the PKP2 protein (p.Gly488Ser). This variant is present in population databases (rs537458442, gnomAD 0.07%). 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: 229142). 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. -

Cardiovascular phenotype

Benign:1

Mar 28, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.6

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.097

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.71

M_CAP

Benign

0.0040

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

PhyloP100

0.45

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.29

REVEL

Benign

0.049

Sift

Benign

0.59

Sift4G

Benign

0.69

Polyphen

0.0020

Vest4

0.26

MutPred

0.42

Gain of glycosylation at G488 (P = 0.0035);

MVP

0.53

MPC

0.15

ClinPred

0.0054

GERP RS

0.51

Varity_R

0.088

gMVP

0.23

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over