rs147240502

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001005242.3(PKP2):c.1460T>G(p.Ile487Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,612,890 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 28 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 7.83

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0121154785).

BP6

Variant 12-32841124-A-C is Benign according to our data. Variant chr12-32841124-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 45035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32841124-A-C is described in Lovd as [Benign]. Variant chr12-32841124-A-C is described in Lovd as [Pathogenic]. Variant chr12-32841124-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00397 (604/152244) while in subpopulation NFE AF= 0.00429 (292/68020). AF 95% confidence interval is 0.00389. There are 5 homozygotes in gnomad4. There are 354 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 604 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3 linkuse as main transcript	c.1460T>G	p.Ile487Ser	missense_variant	6/13	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.1460T>G	p.Ile487Ser	missense_variant	6/13	1	NM_001005242.3	ENSP00000342800	P1	Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

604

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0224

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00480

AC:

1207

AN:

251382

Hom.:

AF XY:

0.00482

AC XY:

655

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0232

Gnomad NFE exome

AF:

0.00533

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00411

AC:

6000

AN:

1460646

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

2948

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0214

Gnomad4 NFE exome

AF:

0.00413

Gnomad4 OTH exome

AF:

0.00272

GnomAD4 genome

AF:

0.00397

AC:

604

AN:

152244

Hom.:

Cov.:

AF XY:

0.00476

AC XY:

354

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0224

Gnomad4 NFE

AF:

0.00429

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00400

Hom.:

Bravo

AF:

0.00233

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00472

AC:

573

EpiCase

AF:

0.00387

EpiControl

AF:

0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 08, 2015	p.Ile531Ser in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 2.6% (170/6614) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs147240502). -
Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Arrhythmogenic right ventricular dysplasia 9

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 01, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2016	Variant summary: The PKP2 c.1592T>G (p.Ile531Ser) variant causes a missense change with 3/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a damaging outcome for this variant. This variant was found in 867/136406 control chromosomes (2 homozygotes) at a frequency of 0.006356, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0004301), suggesting this variant is likely a benign polymorphism. In addition, multiple publications report the variant to co-occur with other potentially pathogenic variants. In the few small pedigrees published, the variant did not segregate within families, leading authors to conclude that this variant could be modulating the effect of another variant or this variant could have low penetrance. Furthermore, functional studies support the variant to have comparable to wild-type function. In addition, multiple reputable clinical diagnostic laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKP2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 16, 2016	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 07, 2016	- -

Family history of cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 18, 2018

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2015

This alteration is classified as 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

Pathogenic

0.76

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

.;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.1

.;M

MutationTaster

Benign

0.82

D;D

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.97

D;D

Vest4

0.88

MVP

0.84

MPC

0.51

ClinPred

0.045

GERP RS

5.2

Varity_R

0.76

gMVP

0.83

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