rs1046116

Positions:

• chr12-32869000-A-G

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.1097T>C​(p.Leu366Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,613,432 control chromosomes in the GnomAD database, including 38,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3000 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35883 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.97

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 (MetaRNN=0.008521527).
• BP6: Variant 12-32869000-A-G is Benign according to our data. Variant chr12-32869000-A-G is described in ClinVar as [Benign]. Clinvar id is 45006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32869000-A-G is described in Lovd as [Benign]. Variant chr12-32869000-A-G is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1097T>C	p.Leu366Pro	missense_variant	4/13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1097T>C	p.Leu366Pro	missense_variant	4/13	1	NM_001005242.3	ENSP00000342800	P1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30093 AN: 152040 Hom.: 2999 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.180 AC: 45239 AN: 251308 Hom.: 4492 AF XY: 0.182 AC XY: 24718 AN XY: 135846

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0294

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.216 AC: 316176 AN: 1461272 Hom.: 35883 Cov.: 33 AF XY: 0.215 AC XY: 156088 AN XY: 726994

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.0277

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.193

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.198 AC: 30112 AN: 152160 Hom.: 3000 Cov.: 32 AF XY: 0.195 AC XY: 14492 AN XY: 74398

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.0328

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.193

Alfa AF: 0.212 Hom.: 8095

Bravo AF: 0.196

TwinsUK AF: 0.230 AC: 852

ALSPAC AF: 0.226 AC: 870

ESP6500AA AF: 0.200 AC: 883

ESP6500EA AF: 0.230 AC: 1979

ExAC AF: 0.180 AC: 21856

Asia WGS AF: 0.111 AC: 384 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Benign:6

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:5

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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 07, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 04, 2019	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Arrhythmogenic right ventricular cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27153395, 19863551, 20864495, 25445213) -

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
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.4
DANN	Benign	0.24
DEOGEN2	Benign	0.087	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.18	T;T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.13
Sift	Benign	0.41	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0	B;B
Vest4		0.10
MPC		0.25
ClinPred		0.0021	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.33

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: rs1046116; hg19: chr12-33021934;