12-32824163-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001005242.3(PKP2):c.1557-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000561 in 1,605,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.74

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 12-32824163-C-G is Pathogenic according to our data. Variant chr12-32824163-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 201989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32824163-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKP2	NM_001005242.3 link	c.1557-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 12	ENST00000340811.9	NP_001005242.2	Q99959-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9 link	c.1557-1G>C		splice_acceptor_variant, intron_variant	Intron 6 of 12	1	NM_001005242.3	ENSP00000342800.5		Q99959-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250198

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135340

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.00000344

AC:

AN:

1453518

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723754

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000966

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:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9

Pathogenic:2

Mar 06, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PS4_supporting -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 7 of the PKP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 17041889, 23911551). This variant is present in population databases (rs78897684, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 19863551, 20400443, 27532257). This variant is also known as 1690-1G>C. ClinVar contains an entry for this variant (Variation ID: 201989). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:2

Jun 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1689-1G>C variant of the PKP2 gene is located at the canonical acceptor splice site of the intronic region. This variant has been reported in at least six individuals affected with arrhythmogenic right ventricular cardiomyopathy/ dysplasia (ARVC/D) (PMID:20400443, 19863551, 27532257, 30790397, 35536239, 36720007). In-silico computational prediction tools suggest that the c.1689-1G>C variant likely leads to acceptor loss (SpliceAI Acceptor loss: 1), resulting in an aberrant or absence of protein product (PMID: 16199547). Loss of function variants are well known to be pathogenic for PKP2 and ClinGen score shows sufficient evidence of haploinsufficiency (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss of function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC/D (PMID:16799251, 22214898, 23514727, 16415378, 27532257) and classified as pathogenic by ClinVar submitters (ClinVar ID:406551, 1072271). This variant is found to be rare (5/281516; 0.001776%) in the general population database, gnomAD and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 201989). Therefore, the c.1689-1G>C variant in the PKP2 gene is classified as pathogenic. -

Jul 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1689-1G>C variant in PKP2 has been reported in 3 individuals with ARVC (Barahona-Dussault 2010, Fressart 2010, Walsh 2017) and has been identified in 5/24016 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs78897684). This variant has also been reported in ClinVar (Variation ID 201989). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner based upon clinical data and predicted impact on protein. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PS4_Supporting. -

not provided

Pathogenic:2

Jul 26, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15489853, 27532257, 27831900, 28523642, 26112193, 23911551, 31402444, 30790397, 31447099, 20400443, 35819174, 34697415) -

Cardiovascular phenotype

Pathogenic:1

Jan 20, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1689-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 8 of the PKP2 gene. This alteration, which is also known as c.1690-1G>C, has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Fressart V et al. Europace, 2010 Jun;12:861-8; Barahona-Dussault C et al. Clin Genet, 2010 Jan;77:37-48; Natarajan P et al. Sci Transl Med, 2016 11;8:364ra151). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: -10

DS_AL_spliceai

1.0

Position offset: -1

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