rs139159464

Variant names:

• chr12-32843314-C-T
• rs139159464
• NM_001005242.3:c.1379-2109G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PP3_Moderate BP6 BS1 BS2

The NM_001005242.3(PKP2):​c.1379-2109G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,365,274 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 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PKP2 NM_001005242.3 intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 0.507
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 12-32843314-C-T is Benign according to our data. Variant chr12-32843314-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45023.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00046 (70/152300) while in subpopulation AFR AF = 0.00166 (69/41564). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1379-2109G>A		intron_variant	Intron 5 of 12	ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1379-2109G>A		intron_variant	Intron 5 of 12	1	NM_001005242.3	ENSP00000342800.5

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 246730 AF XY: 0.0000897

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000420 AC: 51 AN: 1212974 Hom.: 0 Cov.: 29 AF XY: 0.0000432 AC XY: 26 AN XY: 601310

African (AFR) AF: 0.00148 AC: 39 AN: 26284

American (AMR) AF: 0.00 AC: 0 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16892

East Asian (EAS) AF: 0.00 AC: 0 AN: 16804

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30642

Middle Eastern (MID) AF: 0.000224 AC: 1 AN: 4468

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 953392

Other (OTH) AF: 0.000205 AC: 9 AN: 43988

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74478

African (AFR) AF: 0.00166 AC: 69 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:3 Benign:1

May 22, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKP2 c.1379-1G>A variant (rs139159464) is reported in the literature in a control individual from a cardiomyopathy cohort (Kapplinger 2011). This variant is reported in ClinVar (Variation ID: 45023), and is found in the African population with an allele frequency of 0.15% (38/24900 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice acceptor site of intron 5, which is likely to cause exon skipping, but would leave the transcript in frame. However, without functional studies, the effect on splicing is uncertain. Additionally, the predominant isoform in the heart does not include exon 6, and variants in exon 6 may not be associated with disease (Gandjbakhch 2011). Given the lack of clinical and functional data, the significance of the c.1379-1G>A variant is uncertain at this time. References: Gandjbakhch E et al. Plakophilin 2A is the dominant isoform in human heart tissue: consequences for the genetic screening of arrhythmogenic right ventricular cardiomyopathy. Heart. 2011 May;97(10):844-9. Kapplinger JD et al. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol. 2011 Jun 7;57(23):2317-27. -

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 6 c.1379-1G>A: This variant has been reported in the literature in two individuals who underwent exome sequencing, but neither had a diagnosis or features of ARVC (Haggerty 2017 PMID:28471438). This variant is present in 0.1% (38/24900) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-32996248-C-T). This variant is also present in ClinVar (Variation ID:45023). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2). Loss of function variants are a known mechanism of disease for this gene (Rasmussen 2014 PMID:24704780). However, exon 6 does not appear to be spliced in/a coding exon with a different transcript, and there is no additional evidence suggesting pathogenicity at this time. Further studies are needed to understand the impact of this variant. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Uncertain:1 Benign:2

Jul 05, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.1379-1G>A var iant in PKP2 has been identified by our laboratory in 1 Black individual with mi ld LVH, NSVT, and AFib and a family history of DCM and is listed in the ARVC Dat abase (http://arvcdatabase.info) but without additional information. It has also been identified in 0.14% (32/23970) of African chromosomes by the Genome Aggreg ation Consortium (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139159464). PKP2 has two isoforms: a short isoform (PKP2a) missing exon 6 and a long isoform (PKP2b) including exon 6. The short isoform is the predominant form in the hear t, and variants in exon 6 may not be associated with ARVC (Gandjbakhch, 2011). T his variant occurs in the invariant region (+/- 1,2) of the splice consensus seq uence of intron 5 and is predicted to cause altered splicing of exon 6. In summa ry, while the clinical significance of the 1379-1G>A variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS 1_Supporting. -

Jun 03, 2025

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 NM_004572.4 c.1379-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of PKP2 function, however exon 6 is reported to be naturally spliced out (Gandjbakhch_2011), suggesting that this variant is not damaging. This variant is also annotated as PKP2 NM_001005242.3 c.1379-2109G>A, alters a non-conserved deep intronic nucleotide in this transcript. The variant allele was found at a frequency of 8.8e-05 in 1359600 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065). In addition, tissue expression data demonstrated that exon 6 is not expressed in any tested tissues (gnomAD, based on data from the GTEx v10 dataset). The variant, c.1379-1G>A, has been observed in at least one individual affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, however it was also found in healthy controls, and in individuals with other phenotypes (Kapplinger_2011, Dueker_2018, Haggerty_2017, Kobayashi_2017, Yang_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29288195, 21378009, 28471438, 21636032, 28166811, 36129056). ClinVar contains an entry for this variant (Variation ID: 45023). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 09, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.4
DANN	Benign	0.75
Eigen	Benign	0.14
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.043	N
PhyloP100		0.51
GERP RS		1.1
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.73
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

Other links and lift over

dbSNP: rs139159464; hg19: chr12-32996248;