rs149968852

Positions:

• chr12-32796095-A-AG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.980

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.2357+13_2357+14insC		intron_variant		ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.2357+13_2357+14insC		intron_variant		1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31239 AN: 151936 Hom.: 3877 Cov.: 27

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

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.: 33 AF XY: 0.174 AC XY: 125923 AN XY: 725198

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.: 27 AF XY: 0.212 AC XY: 15744 AN XY: 74288

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

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2012	Benign based on high proband frequency (>10%) -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Arrhythmogenic right ventricular dysplasia 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

Cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs149968852; hg19: chr12-32949029;