rs146882581

chr12-32841139-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001005242.3(PKP2):c.1445C>T(p.Thr482Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,612,778 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T482A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22
• Conservation: PhyloP100: 0.694

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022124588).
• BP6: Variant 12-32841139-G-A is Benign according to our data. Variant chr12-32841139-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45033.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=12, Benign=7}. Variant chr12-32841139-G-A is described in Lovd as [Benign]. Variant chr12-32841139-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00387 (589/152288) while in subpopulation AMR AF= 0.0114 (174/15292). AF 95% confidence interval is 0.01. There are 3 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 590 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1445C>T	p.Thr482Met	missense_variant	6/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1445C>T	p.Thr482Met	missense_variant	6/13	1	NM_001005242.3	P1

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 590 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00245 AC: 617 AN: 251334 Hom.: 4 AF XY: 0.00225 AC XY: 305 AN XY: 135830

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.00572

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00263 AC: 3845 AN: 1460490 Hom.: 7 Cov.: 30 AF XY: 0.00258 AC XY: 1876 AN XY: 726700

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00290

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00404 AC XY: 301 AN XY: 74450

Gnomad4 AFR AF: 0.00520

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00278 Hom.: 2

Bravo AF: 0.00430

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00230 AC: 279

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:22

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 04, 2018	Variant summary: PKP2 c.1577C>T (p.Thr526Met) results in a non-conservative amino acid change located in the Armadillo-type fold (IPR016024) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 278492 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 5.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is benign. c.1577C>T has been reported in the literature in individuals affected with Arrhythmia. These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (PKP2, p.L452*; DSP c.969_974delAAAAGA, p.E324_K325del; DES c.359C>A, p.A120D), providing supporting evidence for a benign role. (Rasmussen 2014, Rasmussen 2013, Brodehl 2013). These authors proposed that the variant of interest might modify the phenotype of other pathogenic variants (Rasmussen 2013) although no conclusive evidence supporting this notion has been published. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (1x), likely benign (4x) or VUS (1x). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 18, 2016	- -
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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 25, 2015	p.Thr526Met in exon 7 of PKP2: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (60/10364) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs146882581). -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Aug 14, 2017	BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Arrhythmogenic right ventricular dysplasia 9 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 26, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely 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	Oct 20, 2023	- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 20, 2015	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 26332594, 27153395, 26764160, 21636032, 25637381, 23299917) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PKP2: PM5, BP4, BS2 -

Premature ventricular contraction;C1142166:Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 10, 2019

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1, BP4 -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2018

This alteration is classified as likely 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. -

Familial isolated arrhythmogenic right ventricular dysplasia Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	8.7
Dann	Benign	0.91
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.15
Sift	Benign	0.070	T;D
Sift4G	Benign	0.070	T;T
Polyphen		0.051	B;B
Vest4		0.53
MVP		0.83
MPC		0.18
ClinPred		0.0030	T
GERP RS		2.0
Varity_R		0.076
gMVP		0.30

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: rs146882581; hg19: chr12-32994073; COSMIC: COSV50726327;