rs727504509

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3PP5BS2

The NM_001005242.3(PKP2):c.2352C>T(p.Gly784=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,334 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). Synonymous variant affecting the same amino acid position (i.e. G784G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: -1.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-32796114-G-A is Pathogenic according to our data. Variant chr12-32796114-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178879.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=3}. Variant chr12-32796114-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKP2	NM_001005242.3 linkuse as main transcript	c.2352C>T	p.Gly784=	synonymous_variant	11/13	ENST00000340811.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKP2	ENST00000340811.9 linkuse as main transcript	c.2352C>T	p.Gly784=	synonymous_variant	11/13	1	NM_001005242.3	P1	Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251434

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461194

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PKP2: PM2:Supporting, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Identified in isolation and in conjunction with additional cardiogenetic variants in individuals in the literature, but segregation data are limited or absent at this time (Ali et al., 2018; Dalal et al., 2009); Identified in at least two patients in the literature with ARVC who were homozygous for c.2484 C>T and heterozygous relatives were reported to be unaffected or asymptomatic (Awad et al., 2006; Tan et al., 2010; den Haan et al., 2009); This variant is associated with the following publications: (PMID: 23810883, 28573431, 17041889, 23354045, 29961461, 20857253, 20031617, 30205876, 19358943, 27030002, 31402444, 32180835, 33206225, 33595719, 35059364, 31963859, 33802229, 34079803, 33536939, 28329361, 23671136, 24352520, 24632794) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2017	In a homozygous state, the c.2484C>T variant (rs727504509) has been reported in the medical literature in two individuals with arrhythmogenic right ventricular dysplasia (Awad 2006, Dalal 2009, den Haan 2009, and Tan 2010) as well as an asymptomatic teenager with abnormal EKG findings (Perrin 2013). Individuals who were heterozygous for the variant were unaffected (Awad 2006). Functional evidence indicates that the c.2484C>T variant creates a cryptic splice site that causes a frame shift, which disrupts the last 54 amino acids, adds an additional 48 residues, and alters protein localization and function (Awad 2006 and Kim 2013). The c.2484C>T variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency of 0.0036% in non-Finnish Europeans (identified in 4 out of 111,662 chromosomes) and is listed the ClinVar database with conflicting interpretations of pathogenicity (variant of uncertain significance/likely pathogenic; Variation ID: 178879). Based on the available evidence, the c.2484C>T variant is likely to be pathogenic. Pathogenic variants in PKP2 are typically inherited in an autosomal dominant manner and are associated with arrhythmogenic right ventricular dysplasia 9 (MIM: 609040). Because the c.2484C>T variant is reported to be associated with autosomal recessive arrhythmogenic right ventricular dysplasia, it is unlikely that this variant is responsible for the patientâ€™s phenotype; however, a modifying role cannot be ruled out. -

Arrhythmogenic right ventricular dysplasia 9

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 12, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in partial skipping of exon 12 and introduces a new termination codon (PMID: 17041889). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 178879). This variant has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy or clinical features of this condition in the homozygous state (PMID: 17041889, 23810883, 29961461). This variant is present in population databases (rs727504509, gnomAD 0.004%). This sequence change affects codon 828 of the PKP2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKP2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.2484C>T variant (also known as p.G828G), located in coding exon 12 of the PKP2 gene, results from a C to T substitution at nucleotide position 2484. This nucleotide substitution does not change the glycine at codon 828. This variant has been reported in the homozygous state in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, it has also been reported in an asymptomatic homozygote, as well as in unaffected heterozygotes (Awad MM et al. Hum. Mutat., 2006 Nov;27:1157; den Haan AD et al. Circ Cardiovasc Genet, 2009 Oct;2:428-35;Perrin MJ et al. J Am Coll Cardiol, 2013 Nov;62:1772-9; Ali M et al. Indian Heart J 2018 Oct;70:421-426). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies demonstrated splicing impact in the majority of transcripts derived from the variant allele (Awad MM et al. Hum. Mutat., 2006 Nov;27:1157; Kim C et al. Nature, 2013 Feb;494:105-10). Based on the supporting evidence, this variant is likely to be pathogenic for arrhythmogenic right ventricular cardiomyopathy (ARVC) when present along with a second pathogenic variant on the other allele; however, its clinical significance in the heterozygous state is unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2019

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly828Gly variant in PKP2 has been reported as homozygous in 1 adult with ARVC and as heterozygous in her unaffected parents (Awad 2006, Dalal 2009, den Haan 2009, Tan 2010) and as homozygous in 1 asymptomatic teenager with RBBB and other abnormal EKG findings (Perrin 2013). It was also identified in 2/66738 European chromosomes by the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/; dbSNP rs727504509). mRNA studies showed that the 2484C>T variant results in a 7 bp deletion at the end of exon 12, resulting in a frameshift that extends the coding sequence by 145 bp (48 amino acids; Awad 2006, Kim 2013). While it is unclear if this variant would be disease-causing in isolation, the available evidence suggests that it is likely pathogenic when seen in homozygosity or with a second PKP2 variant. However, additional studies are needed to fully assess the clinical significance of this variant. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 22, 2023

This synonymous variant in the PKP2 protein is predicted to impact RNA splicing by creating a new splice donor site 7 nucleotides upstream from the native donor site. A functional RNA study in cells derived from a homozygous individual has shown that this variant causes aberrant splicing and deletion of the last 7 nucleotides in exon 12 (PMID: 17041889). The ensuing frameshift is expected to disrupt the last 54 amino acids of PKP2 protein and extend the C-terminus by 48 amino acids. This variant has been reported in homozygosity in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 17041889, 29961461). One of the proband's three heterozygous, teenaged children were unaffected. This variant has been observed in multiple individuals from the same cohort (PMID: 19358943, 20031617, 20857253, 23671136, 23810883, 23810894) and it is not clear how many unrelated, affected individuals are known to carry this variant. This variant has been identified in 5/282794 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with autosomal recessive ARVC, the available evidence is insufficient to determine the role of this variant in autosomal dominant ARVC conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

Dann

Benign

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over