rs397516994
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_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
NM_001005242.3 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing 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;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
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 | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1378+1G>C | splice_donor_variant | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1378+1G>C | splice_donor_variant | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250730Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135578
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457724Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 725404
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Apr 25, 2014 | - - |
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. - |
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:2
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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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). - |
not provided Pathogenic:2
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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 47
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at