12-32896576-C-T

Variant names:

• chr12-32896576-C-T
• rs201210997
• NM_001005242.3:c.156G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001005242.3(PKP2):​c.156G>A​(p.Lys52Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,590,896 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: PKP2 NM_001005242.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.04
• Publications: 3 publications found

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]

PKP2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000309487 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 12-32896576-C-T is Benign according to our data. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32896576-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 45030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.001 (153/152304) while in subpopulation AMR AF = 0.00758 (116/15304). AF 95% confidence interval is 0.00646. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.156G>A	p.Lys52Lys	synonymous_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.156G>A	p.Lys52Lys	synonymous_variant	Exon 1 of 13	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152186 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00140 AC: 300 AN: 214976 AF XY: 0.000927

Gnomad AFR exome AF: 0.000160

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00266

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000928

GnomAD4 exome AF: 0.000394 AC: 567 AN: 1438592 Hom.: 4 Cov.: 32 AF XY: 0.000335 AC XY: 240 AN XY: 715798

African (AFR) AF: 0.0000305 AC: 1 AN: 32738

American (AMR) AF: 0.00795 AC: 351 AN: 44146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00427 AC: 167 AN: 39140

South Asian (SAS) AF: 0.0000590 AC: 5 AN: 84812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4520

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109010

Other (OTH) AF: 0.000586 AC: 35 AN: 59754

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152304 Hom.: 1 Cov.: 33 AF XY: 0.00103 AC XY: 77 AN XY: 74462

African (AFR) AF: 0.000313 AC: 13 AN: 41584

American (AMR) AF: 0.00758 AC: 116 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00272 AC: 14 AN: 5146

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.000378 Hom.: 0

Bravo AF: 0.00191

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Benign:6

Apr 25, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Sep 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Aug 14, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Lys52Lys in exon 1 of PKP2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1% (78/8192) of Lati no chromosomes, including 1 homozygote, by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201210997). -

Dec 03, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKP2 c.156G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 242920 control chromosomes, predominantly at a frequency of 0.0078 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 7.25 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 Latino origin. c.156G>A has been reported in the literature in individuals affected with Cardiomyopathy (Wu_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Mar 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31402444, 26332594, 19302745) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiomyopathy Benign:1

Mar 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKP2-related disorder Benign:1

Aug 07, 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). -

Cardiovascular phenotype Benign:1

Dec 08, 2014

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
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		1.0
PromoterAI		-0.034	Neutral
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs201210997; hg19: chr12-33049510;