rs139159464

chr12-32843314-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Moderate PP3_Moderate BS1 BS2

The ENST00000070846.11(PKP2):c.1379-1G>A variant causes a splice acceptor 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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 ENST00000070846.11 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.507

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 Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.04950869 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of -43, new splice context is: catttgctgtgttcataaAGgag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3	c.1379-2109G>A		intron_variant		ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9	c.1379-2109G>A		intron_variant		1	NM_001005242.3	P1

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

GnomAD3 exomes AF: 0.000109 AC: 27 AN: 246730 Hom.: 0 AF XY: 0.0000897 AC XY: 12 AN XY: 133708

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 SAS 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

Gnomad4 AFR exome AF: 0.00148

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000105

Gnomad4 OTH exome AF: 0.000205

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

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000749 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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2021	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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2019	Variant summary: PKP2 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 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. In addition, exon 6 is naturally spliced out (Gandjbakhch_2011), suggesting this variant is not damaging. The observed variant frequency within African control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1379-1G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Kapplinger_2011, Dueker_2018, Haggerty_2017, Kobayashi_2017). 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. Two ClinVar submissions (evaluation after 2014) cite the variant once as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 05, 2018	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. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 08, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2019

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
MutationTaster	Benign	1.0	N;N
GERP RS		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs139159464; hg19: chr12-32996248;