rs199601548

Variant names:

• chr12-32896548-G-T
• rs199601548
• NM_001005242.3:c.184C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001005242.3(PKP2):​c.184C>A​(p.Gln62Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,584,186 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: PKP2 NM_001005242.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:2
• Conservation: PhyloP100: 1.92

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012146056).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000276 (395/1431906) while in subpopulation MID AF= 0.000442 (2/4526). AF 95% confidence interval is 0.000308. There are 0 homozygotes in gnomad4_exome. There are 182 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.184C>A	p.Gln62Lys	missense_variant	Exon 1 of 13	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.184C>A	p.Gln62Lys	missense_variant	Exon 1 of 13	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000141 AC: 30 AN: 212730 Hom.: 0 AF XY: 0.000160 AC XY: 19 AN XY: 118748

Gnomad AFR exome AF: 0.0000821

Gnomad AMR exome AF: 0.0000618

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000855

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.000276 AC: 395 AN: 1431906 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 182 AN XY: 712048

Gnomad4 AFR exome AF: 0.0000624

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.000337

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000461

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000358 AC: 3

ExAC AF: 0.000151 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:7 Benign:1

Apr 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKP2 c.184C>A; p.Gln62Lys variant (rs199601548) variant has been published in multiple unrelated individuals affected with arrhythmogenic right ventricular dysplasia or cardiomyopathy (Bauce 2010, Cerrone 2014, Christensen 2009, Garcia-Pavia 2011, Lahtinen 2011, Sanchez 2016). However, segregation studies demonstrate this variant has been detected in unaffected individuals and failed to segregate with ARVC in at least one family (Bauce 2010, Christensen 2010). Additionally, this variant was detected on the opposite chromosome from a loss of function PKP2 variant in an affected family (Bauce 2010). The variant is reported in the ClinVar database (Variation ID: 161332) and is found in the non-Finnish European population with an allele frequency of 0.029% (33/112,560 alleles) in the Genome Aggregation Database. The glutamine at codon 62 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.441). Functional studies show this variant disrupted interactions with desmoplakin and decreased function (Cerrone 2014, Hall 2009). Due to conflicting information, the clinical significance of the p.Gln62Lys variant is uncertain at this time. References: Bauce B et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010 Jan;7(1):22-9. PMID: 20129281. Cerrone M et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation. 2014 Mar 11;129(10):1092-103. PMID: 24352520. Christensen AH et al. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders? Cardiology. 2010;115(2):148-54. PMID: 19955750. Garcia-Pavia P et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011 Nov;97(21):1744-52. PMID: 21859740. Hall C et al. Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability. Cell Commun Adhes. 2009;16(1-3):15-27. PMID: 19533476. Lahtinen AM et al. Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2011 Aug;8(8):1214-21. PMID: 21397041. Sanchez O et al. Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. PLoS One. 2016 Dec 8;11(12):e0167358. PMID: 27930701. -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKP2 NM_004572.3 exon 1 p.Gln62Lys (c.184C>A): This variant has been reported in the literature in at least 6 individuals with ARVC, at least two of which also carried additional disease-causing cardiogenetic variants (van Tintelen 2006 PMID:16567567, Lahtinen 2008 PMID:17521752, Fidler 2009 PMID:18662195, Bauce 2010 PMID:20129281, Christensen 2010 PMID:19955750). Segregation of this variant within families is inconclusive; the variant has been shown to segregate with disease is a small number of families but did not segregate with disease in others (Lahtinen 2008 PMID:17521752, Bauce 2010 PMID:20129281. Christensen 2010 PMID:19955750). This variant has also been reported in an individual with DCM, in an individual with Brugada syndrome, and in a sudden death case (Garcia-Pavia 2011 PMID:21859740, Cerrone 2014 PMID:24352520, Christiansen 2016 PMID:27650956). This variant is present in 0.02% (33/112560) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-33049482-G-T) and is present in ClinVar (Variation ID:161332). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro studies have shown subcellular localization of this mutant protein similar to wildtype protein, but functional studies have demonstrated abnormal interaction of the protein with desmoplakin and decreased sodium currents, suggesting that this variant may impact the protein (Fidler 2009 PMID:18662195, Hall 2009 PMID:19533476, Cerrone 2014 PMID:24352520). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 9, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting . PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:19533476). -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 17, 2019

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 31, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:5

Sep 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_supporting -

Sep 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported in multiple unrelated individuals with ARVC, DCM, Brugada syndrome, HCM, and/or sudden death both in published literature and in individuals referred for testing at GeneDx; however, many of these individuals harbor additional variants in the PKP2 gene or other cardiac genes (PMID: 16567567, 17521752, 18662195, 20129281, 19955750, 20152563, 24070718, 26138720, 21859740, 24352520, 27930701, 32917565, 36178741); Published segregation studies show this variant has been observed in both affected and unaffected adult relatives (PMID:17521752, 20129281) and has failed to segregate with ARVC in at least one family (PMID: 19955750); Published functional studies demonstrate p.(Q62K) mutant protein disrupts proper desmosome assembly and leads to reduced sodium current (PMID: 19533476, 24352520); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24618965, 29456632, 23299917, 24352520, 20152563, 24070718, 17521752, 21859740, 26138720, 18662195, 26718681, 21397041, 25637381, 23651034, 27930701, 20129281, 27650965, 30765282, 31737537, 31118017, 30847666, 30764827, 34426522, 30483629, 32880476, 32917565, 25395996, 36178741, 16567567, 19955750, 19533476, 32466575, 38540378) -

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1 Benign:1

Apr 18, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Feb 27, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKP2 c.184C>A (p.Gln62Lys) results in a conservative amino acid change in 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 0.00014 in 212730 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00014 vs 0.00065), allowing no conclusion about variant significance. c.184C>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Lahtinen_2008, Christensen_2009, Bauce_2010), Brugada Syndrome (Cerrone_2014), DCM (Garcia-Pavia_2011, van der Meulen_2022) and HCM (Sanchez_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. However, this variant does not co-segregate with disease in at least one family (Christensen_2009). Co-occurrence with a pathogenic variant has been reported (PKP2 c.2119C>T, Q707X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant disrupted interactions with desmoplakin and decreased sodium current (Hall_2009, Cerrone_2014). The following publications have been ascertained in the context of this evaluation (PMID: 19955750, 20129281, 21397041, 21859740, 27930701, 24352520, 19533476, 36178741). ClinVar contains an entry for this variant (Variation ID: 161332). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Long QT syndrome Uncertain:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: BP1 -

Cardiovascular phenotype Uncertain:1

Feb 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q62K variant (also known as c.184C>A), located in coding exon 1 of the PKP2 gene, results from a C to A substitution at nucleotide position 184. The glutamine at codon 62 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a variety of clinical phenotypes including arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomypathy (DCM), Brugada syndrome, sudden unexplained death, and hypertrophic cardiomyopathy (HCM), and is often seen with additional alterations in PKP2 and other cardiac-related genes (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Garcia-Pavia P et al. Heart, 2011 Nov;97:1744-52; Cerrone M et al. Circulation, 2014 Mar;129:1092-103; Christiansen SL et al. Eur. J. Hum. Genet., 2016 12;24:1797-1802; Sanchez O et al. PLoS ONE, 2017 Feb;12:e0171893). This alteration has also been detected in unaffected family members and absent in affected relatives with ARVC (Lahtinen AM et al. Int. J. Cardiol., 2008 May;126:92-100; Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Christensen AH et al. Cardiology, 2010 Dec;115:148-54). In addition, this variant has been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Dewey FE et al. JAMA, 2014 Mar;311:1035-45). In functional studies, observed results have included decreased connexin43 expression, defects in desmosome assembly, and reduced sodium current (Fidler LM et al. J. Cell. Mol. Med., 2009 Oct;13:4219-28; Hall C et al. Cell Commun. Adhes., 2009;16:15-27; Cerrone M et al. Circulation, 2014 Mar;129:1092-103). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.39	T;T
Sift4G	Uncertain	0.028	D;D
Polyphen		0.47	P;P
Vest4		0.51
MVP		0.81
MPC		0.35
ClinPred		0.036	T
GERP RS		4.1
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: rs199601548; hg19: chr12-33049482;