rs397516994

Positions:

• chr12-32850765-C-G
• chr12-32850765-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001005242.3(PKP2):​c.1378+1G>C variant causes a splice donor change. The variant allele was found at a frequency of 0.00000274 in 1,457,724 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PKP2 NM_001005242.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.33

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.9, offset of -46, new splice context is: cagGTgctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32850765-C-G is Pathogenic according to our data. Variant chr12-32850765-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32850765-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP2	NM_001005242.3	c.1378+1G>C		splice_donor_variant		ENST00000340811.9	NP_001005242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP2	ENST00000340811.9	c.1378+1G>C		splice_donor_variant		1	NM_001005242.3	ENSP00000342800	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250730 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135578

Gnomad AFR exome AF: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457724 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 725404

Gnomad4 AFR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	The c.1378+1G>C intronic variant of the PKP2 gene is located at the canonical donor splice site of intron 5. This variant has been reported in numerous (>15) individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 27194543, 23810894, 23671136, 20400443, 33968641, 28588093, 30830208, 34469894, 30677492, 24704780, 23810883, 25820315). This variant was also identified in the proband, mother and brother in a family, while the mother and brother were asymptomatic carriers (PMID: 33238575). An alteration at the same position, c.1378+1G>A, has also been reported to cause ARVC (PMID:18662195). In-silico computational prediction tools suggest that the c.1378+1G>C variant likely leads to donor loss and disturbs normal splicing, resulting in an absent of disrupted protein product (PMID: 16199547). Loss of function variants are known to be pathogenic for PKP2 gene (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: 26701096, 15489853, 17010805, 19358943, 20152563) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 517335, 202019, 202035). This variant is found to be rare (1/250730; 0.000003988) in the general population database, gnomAD and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 45022). Therefore, the c.1378+1G>C variant in the PKP2 gene is classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Apr 25, 2014	- -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 03, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 45022). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18662195, 20400443, 31386562). This variant is present in population databases (rs397516994, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 5 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, 23911551). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Mar 06, 2024	The PKP2 c.1378+1G>C variant has been reported in several individuals affected with ARVC (Costa S et al., PMID: 33238575; Fidler LM et al., PMID: 18662195; Fressart V et al., PMID: 20400443; Medeiros-Domingo A et al., PMID: 27194543; van Lint FHM et al., PMID: 31386562). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by six submitters and is only observed on 1/250,730 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on PKP2 function. Additionally, another variant in the same nucleotide, c.1378+1G>A, has been described in an affected individual and is considered pathogenic (Fidler LM et al., PMID: 18662195, ClinVar Variation ID: 923177). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease AND Non-canonical splice site variant demonstrated to result in loss-of-function (ref); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23671136, 27194543, 20400443, 23810894, 23810883, 30790397, 31386562, 31402444, 33238575, 30677492, 33232181) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1378+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the PKP2 gene. This mutation has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Fressart V et al. Europace. 2010; 12:861-8; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013; 6:569-78; Medeiros-Domingo A et al. Europace, 2017 Jun;19:1063-1069; Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800; Costa S et al. J Clin Med, 2020 Nov;9:). In addition, an alteration at the same position, c.1378+1G>A, has also been reported in association with ARVC (Fidler LM J et al. Cell Mol Med. 2009; 13:4219-28). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: 47
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516994; hg19: chr12-33003699;