rs143004808

chr12-32896656-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005242.3(PKP2):c.76G>A(p.Asp26Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 1,563,166 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (98 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.68

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=0.0076743364).
• BP6: Variant 12-32896656-C-T is Benign according to our data. Variant chr12-32896656-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896656-C-T is described in Lovd as [Benign]. Variant chr12-32896656-C-T is described in Lovd as [Likely_benign]. Variant chr12-32896656-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00705 (1074/152332) while in subpopulation NFE AF= 0.00912 (620/68018). AF 95% confidence interval is 0.00852. There are 12 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1076 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.76G>A	p.Asp26Asn	missense_variant	1/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.76G>A	p.Asp26Asn	missense_variant	1/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1076 AN: 152214 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00846 AC: 1427 AN: 168710 Hom.: 14 AF XY: 0.00846 AC XY: 788 AN XY: 93116

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00588

Gnomad ASJ exome AF: 0.0452

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00389

Gnomad FIN exome AF: 0.00252

Gnomad NFE exome AF: 0.00974

Gnomad OTH exome AF: 0.00956

GnomAD4 exome AF: 0.00944 AC: 13313 AN: 1410834 Hom.: 98 Cov.: 32 AF XY: 0.00933 AC XY: 6525 AN XY: 699498

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00549

Gnomad4 ASJ exome AF: 0.0460

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.00395

Gnomad4 FIN exome AF: 0.00306

Gnomad4 NFE exome AF: 0.00969

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.00705 AC: 1074 AN: 152332 Hom.: 12 Cov.: 33 AF XY: 0.00652 AC XY: 486 AN XY: 74490

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.0498

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00912

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0111 Hom.: 1

Bravo AF: 0.00752

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.000965 AC: 4

ESP6500EA AF: 0.00683 AC: 56

ExAC AF: 0.00592 AC: 696

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely 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	Apr 03, 2017	- -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 08, 2011	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2015	p.Asp26Asn in exon 1 of PKP2: This variant is not expected to have clinical sign ificance because it has been identified in 2.3% (349/15114) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs143004808). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2014	- -

Arrhythmogenic right ventricular dysplasia 9 Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 24055113, 19955750, 25637381, 27153395, 16567567, 24352520, 19597050, 23299917, 20400443, 20829228, 27884173, 26656175, 26332594) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PKP2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -

Arrhythmogenic right ventricular cardiomyopathy Benign:2

Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiomyopathy Benign:2

Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2018	- -

Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 28, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2015

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	Uncertain	0.43
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0077	T;T
MetaSVM	Uncertain	0.033	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.17	T;D
Polyphen		0.99	D;D
Vest4		0.30
MVP		0.90
MPC		0.63
ClinPred		0.019	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.52

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: rs143004808; hg19: chr12-33049590;