rs74072938

Positions:

• chr12-32802396-G-A
• chr12-32802396-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005242.3(PKP2):​c.2167+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,010 control chromosomes in the GnomAD database, including 1,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (736 hom., cov: 32)
  • Exomes 𝑓: 0.017 (955 hom.)
• Consequence: PKP2 NM_001005242.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004315
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.47

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-32802396-G-A is Benign according to our data. Variant chr12-32802396-G-A is described in ClinVar as [Benign]. Clinvar id is 45064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32802396-G-A is described in Lovd as [Benign]. Variant chr12-32802396-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.2167+7C>T		splice_region_variant, intron_variant		ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.2167+7C>T		splice_region_variant, intron_variant		1	NM_001005242.3	ENSP00000342800	P1

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 9345 AN: 151798 Hom.: 739 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.00777

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0475

GnomAD3 exomes AF: 0.0278 AC: 6997 AN: 251360 Hom.: 370 AF XY: 0.0262 AC XY: 3560 AN XY: 135854

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00212

Gnomad SAS exome AF: 0.0474

Gnomad FIN exome AF: 0.00944

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0174 AC: 25452 AN: 1461094 Hom.: 955 Cov.: 30 AF XY: 0.0177 AC XY: 12858 AN XY: 726902

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.0468

Gnomad4 FIN exome AF: 0.00965

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0249

GnomAD4 genome AF: 0.0616 AC: 9355 AN: 151916 Hom.: 736 Cov.: 32 AF XY: 0.0600 AC XY: 4456 AN XY: 74254

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.0276

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.0435

Gnomad4 FIN AF: 0.00777

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0470

Alfa AF: 0.0379 Hom.: 223

Bravo AF: 0.0685

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0126

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 03, 2011	The 2299+7C>T variant in PKP2 is not expected to have clinical significance beca use it has been reported at a frequency of ~25% in a Black population and at a f requency of ~1% in a White population (dbSNP-rs74072938, Li 2010). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Arrhythmogenic right ventricular dysplasia 9 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.89
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0060
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: rs74072938; hg19: chr12-32955330;