rs75909145

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001005242.3(PKP2):c.209G>T(p.Ser70Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 1,549,506 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S70R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 39 hom., cov: 33)

Exomes 𝑓: 0.025 ( 524 hom. )

Consequence

PKP2
NM_001005242.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.796

Publications

16 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:

ENSG00000309487 (HGNC:):

ENSG00000309487 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021330118).

BP6

Variant 12-32896523-C-A is Benign according to our data. Variant chr12-32896523-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0193 (2932/152236) while in subpopulation NFE AF = 0.0283 (1926/68008). AF 95% confidence interval is 0.0273. There are 39 homozygotes in GnomAd4. There are 1364 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2932 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.209G>T	p.Ser70Ile	missense_variant	Exon 1 of 13	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.209G>T	p.Ser70Ile	missense_variant	Exon 1 of 13	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2936

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00551

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.0409

Gnomad EAS

AF:

0.000779

Gnomad SAS

AF:

0.0290

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0212

AC:

3960

AN:

186782

AF XY:

0.0226

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0401

Gnomad EAS exome

AF:

0.000378

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.0260

Gnomad OTH exome

AF:

0.0221

GnomAD4 exome

AF:

0.0253

AC:

35288

AN:

1397270

Hom.:

524

Cov.:

AF XY:

0.0254

AC XY:

17610

AN XY:

693138

show subpopulations

African (AFR)

AF:

0.00290

AC:

AN:

30014

American (AMR)

AF:

0.0136

AC:

556

AN:

40974

Ashkenazi Jewish (ASJ)

AF:

0.0402

AC:

974

AN:

24236

East Asian (EAS)

AF:

0.000340

AC:

AN:

35324

South Asian (SAS)

AF:

0.0293

AC:

2359

AN:

80404

European-Finnish (FIN)

AF:

0.0156

AC:

586

AN:

37566

Middle Eastern (MID)

AF:

0.0325

AC:

143

AN:

4396

European-Non Finnish (NFE)

AF:

0.0268

AC:

29097

AN:

1086366

Other (OTH)

AF:

0.0254

AC:

1474

AN:

57990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1707

3413

5120

6826

8533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1064

2128

3192

4256

5320

<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:

0.0193

AC:

2932

AN:

152236

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00447

AC:

186

AN:

41568

American (AMR)

AF:

0.0187

AC:

287

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0409

AC:

142

AN:

3470

East Asian (EAS)

AF:

0.000781

AC:

AN:

5124

South Asian (SAS)

AF:

0.0282

AC:

136

AN:

4824

European-Finnish (FIN)

AF:

0.0183

AC:

194

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0283

AC:

1926

AN:

68008

Other (OTH)

AF:

0.0223

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

148

297

445

594

742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0242

Hom.:

Bravo

AF:

0.0183

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.00368

AC:

ESP6500EA

AF:

0.0261

AC:

212

ExAC

AF:

0.0197

AC:

2330

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 06, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ser70Ile in exon 1 of PKP2: This variant is classified as benign based on its hi gh frequency in the general population (NHLBI Exome sequencing project, http://e vs.gs.washington.edu/EVS). -

Dec 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP6 -

Arrhythmogenic right ventricular dysplasia 9

Benign:6

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28472724, 21606390, 20031617, 19955750) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Mar 13, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 08, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.085

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

L;L

PhyloP100

0.80

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.28

B;B

Vest4

0.25

MPC

0.28

ClinPred

0.0029

GERP RS

3.2

PromoterAI

-0.052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.43

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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