dbSNP rs149968852: PKP2:c.2357+13_2357+14insC (chr12-32796095-A-AG) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001005242.3(PKP2):c.2357+13_2357+14insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,609,152 control chromosomes in the GnomAD database, including 30,631 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3884 hom., cov: 27)

Exomes 𝑓: 0.17 ( 26747 hom. )

Consequence

PKP2
NM_001005242.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.980

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 -16 ACMG points.

BP6

Variant 12-32796095-A-AG is Benign according to our data. Variant chr12-32796095-A-AG is described in ClinVar as [Likely_benign]. Clinvar id is 45070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.2357+13_2357+14insC		intron_variant	Intron 11 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.2357+13_2357+14insC		intron_variant	Intron 11 of 12	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31239

AN:

151936

Hom.:

3877

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.566

Gnomad SAS

AF:

0.333

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.159

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.177

GnomAD3 exomes

AF:

0.211

AC:

52961

AN:

251360

Hom.:

7322

AF XY:

0.212

AC XY:

28739

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.290

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.155

Gnomad EAS exome

AF:

0.554

Gnomad SAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.176

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

AF:

0.170

AC:

247999

AN:

1457096

Hom.:

26747

Cov.:

AF XY:

0.174

AC XY:

125923

AN XY:

725198

show subpopulations

Gnomad4 AFR exome

AF:

0.283

Gnomad4 AMR exome

AF:

0.168

Gnomad4 ASJ exome

AF:

0.155

Gnomad4 EAS exome

AF:

0.567

Gnomad4 SAS exome

AF:

0.324

Gnomad4 FIN exome

AF:

0.171

Gnomad4 NFE exome

AF:

0.140

Gnomad4 OTH exome

AF:

0.187

GnomAD4 genome

AF:

0.206

AC:

31248

AN:

152056

Hom.:

3884

Cov.:

AF XY:

0.212

AC XY:

15744

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.179

Gnomad4 ASJ

AF:

0.159

Gnomad4 EAS

AF:

0.566

Gnomad4 SAS

AF:

0.330

Gnomad4 FIN

AF:

0.182

Gnomad4 NFE

AF:

0.137

Gnomad4 OTH

AF:

0.183

Alfa

AF:

0.156

Hom.:

491

Bravo

AF:

0.206

Asia WGS

AF:

0.418

AC:

1450

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Benign based on high proband frequency (>10%) -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 9

Benign:3

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jun 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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