rs146708884

chr12-32896558-C-Achr12-32896558-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.174G>T(p.Glu58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,589,246 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E58G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (56 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.66

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=0.0050928295).
• BP6: Variant 12-32896558-C-A is Benign according to our data. Variant chr12-32896558-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 45043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896558-C-A is described in Lovd as [Benign]. Variant chr12-32896558-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00652 (993/152286) while in subpopulation NFE AF= 0.00375 (255/68024). AF 95% confidence interval is 0.00337. There are 31 homozygotes in gnomad4. There are 697 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 993 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.174G>T	p.Glu58Asp	missense_variant	1/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.174G>T	p.Glu58Asp	missense_variant	1/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 993 AN: 152168 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00549 AC: 1187 AN: 216324 Hom.: 13 AF XY: 0.00587 AC XY: 707 AN XY: 120518

Gnomad AFR exome AF: 0.000792

Gnomad AMR exome AF: 0.000882

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00481

GnomAD4 exome AF: 0.00451 AC: 6480 AN: 1436960 Hom.: 56 Cov.: 32 AF XY: 0.00439 AC XY: 3136 AN XY: 714878

Gnomad4 AFR exome AF: 0.000462

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.00174

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.0407

Gnomad4 NFE exome AF: 0.00399

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152286 Hom.: 31 Cov.: 33 AF XY: 0.00936 AC XY: 697 AN XY: 74440

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0627

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00301 Hom.: 0

Bravo AF: 0.00203

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00287 AC: 24

ExAC AF: 0.00632 AC: 753

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2015	p.Glu58Asp in exon 1 of PKP2: This variant is not expected to have clinical sign ificance because it was detected in 6.3% (284/4446) Finnish chromosomes, includi ng 5 homozygotes, and 0.7% (377/51932) of European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146708884). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PKP2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Arrhythmogenic right ventricular dysplasia 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely 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 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 11, 2021	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 13, 2018

- -

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	0.26
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.94	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.63	P;P
Vest4		0.33
MutPred		0.20		Gain of phosphorylation at S53 (P = 0.187);Gain of phosphorylation at S53 (P = 0.187);
MVP		0.84
MPC		0.22
ClinPred		0.011	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.21
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146708884; hg19: chr12-33049492;