12-32824092-C-T

Variant names:

• chr12-32824092-C-T
• rs146102241
• NM_001005242.3:c.1627G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001005242.3(PKP2):​c.1627G>A​(p.Val543Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,611,974 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (17 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:21
• Conservation: PhyloP100: 3.10

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011907041).
• BP6: Variant 12-32824092-C-T is Benign according to our data. Variant chr12-32824092-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36681.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=9, Benign=6}. Variant chr12-32824092-C-T is described in Lovd as [Pathogenic]. Variant chr12-32824092-C-T is described in Lovd as [Benign]. Variant chr12-32824092-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (366/152282) while in subpopulation NFE AF = 0.00357 (243/68026). AF 95% confidence interval is 0.0032. There are 1 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1627G>A	p.Val543Ile	missense_variant	Exon 7 of 13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1627G>A	p.Val543Ile	missense_variant	Exon 7 of 13	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00245 AC: 616 AN: 251180 AF XY: 0.00236

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00389 AC: 5685 AN: 1459692 Hom.: 17 Cov.: 29 AF XY: 0.00380 AC XY: 2762 AN XY: 726364

Gnomad4 AFR exome AF: 0.000778 AC: 26 AN: 33438

Gnomad4 AMR exome AF: 0.00268 AC: 120 AN: 44718

Gnomad4 ASJ exome AF: 0.0108 AC: 282 AN: 26114

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39694

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86216

Gnomad4 FIN exome AF: 0.000169 AC: 9 AN: 53232

Gnomad4 NFE exome AF: 0.00449 AC: 4988 AN: 1110194

Gnomad4 Remaining exome AF: 0.00431 AC: 260 AN: 60322

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74454

Gnomad4 AFR AF: 0.00113 AC: 0.00113144 AN: 0.00113144

Gnomad4 AMR AF: 0.00203 AC: 0.00202588 AN: 0.00202588

Gnomad4 ASJ AF: 0.0112 AC: 0.0112392 AN: 0.0112392

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000189 AC: 0.000188537 AN: 0.000188537

Gnomad4 NFE AF: 0.00357 AC: 0.00357216 AN: 0.00357216

Gnomad4 OTH AF: 0.00189 AC: 0.00189036 AN: 0.00189036

Alfa AF: 0.00382 Hom.: 0

Bravo AF: 0.00247

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00236 AC: 287

EpiCase AF: 0.00403

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:21

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Feb 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val587Ile in exon 8 of PKP2: This variant was initially believed to be likely disease causing based on its presence in 2 probands with ARVD/C and absence from 600 control chromosomes (Den Hann 2009, Basso 2006, Albuisson 2007). However, s everal studies identified this variant in 0.2%-0.8% of healthy control chromosom es (Christensen 2010: 3/1300; Fressart 2010: 3/600; Barahona-Dussault 2010: 0.08 %). Furthermore, it has been identified in 0.4% (252/66718) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs146102241). In summary, we cannot rule out that this variant modifies dis ease severity, but believe that it is unlikely disease causing when present in i solation. -

Aug 22, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKP2 c.1759G>A (p.Val587Ile) results in a conservative amino acid change located in the Armadillo (IPR000225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 254134 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Cardiomyopathy phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1759G>A has been reported in the literature in individuals affected with Cardiomyopathy (DenHaan_2009, Haas_2015, teRiele_2013, Baskin_2013, Basso_2006, Leong_2017, Connell_2018), but also in controls (Basso_2006, Christensen_2009, Fressart_2010, Kapplinger_2011). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in terms of stable expression and localization to the cell membrane (Kirchner_2012). Eleven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=5) and benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 21, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 9 Uncertain:1 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKP2: BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 15, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31402444, 24055113, 24585727, 19955750, 22781308, 23299917, 20400443, 25637381, 21859740, 16774985, 19863551, 27153395, 26332594, 30656044) -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1 Benign:2

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Allele frequency may indicate a low penetrance or likely benign variant -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiomyopathy Benign:2

Mar 13, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKP2-related disorder Benign:1

Mar 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ventricular tachycardia Benign:1

Mar 26, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 10, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.25	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T;T
Sift4G	Benign	0.23	T;T
Polyphen		1.0	D;D
Vest4		0.31
MVP		0.71
MPC		0.60
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.51
Mutation Taster		=72/28	polymorphism

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: rs146102241; hg19: chr12-32977026;