rs397514042
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_024422.6(DSC2):c.631-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000026 in 1,613,508 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
DSC2
NM_024422.6 splice_acceptor, intron
NM_024422.6 splice_acceptor, intron
Scores
3
1
3
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.28
Genes affected
DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.8, offset of 25, new splice context is: tgcctttgcaacaactccAGatg. 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 18-31087815-T-C is Pathogenic according to our data. Variant chr18-31087815-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16850.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3, Likely_pathogenic=4}. Variant chr18-31087815-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.631-2A>G | splice_acceptor_variant, intron_variant | ENST00000280904.11 | NP_077740.1 | |||
DSC2 | NM_004949.5 | c.631-2A>G | splice_acceptor_variant, intron_variant | NP_004940.1 | ||||
DSC2 | NM_001406506.1 | c.202-2A>G | splice_acceptor_variant, intron_variant | NP_001393435.1 | ||||
DSC2 | NM_001406507.1 | c.202-2A>G | splice_acceptor_variant, intron_variant | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.631-2A>G | splice_acceptor_variant, intron_variant | 1 | NM_024422.6 | ENSP00000280904.6 | ||||
DSC2 | ENST00000251081.8 | c.631-2A>G | splice_acceptor_variant, intron_variant | 1 | ENSP00000251081.6 | |||||
DSC2 | ENST00000648081.1 | c.202-2A>G | splice_acceptor_variant, intron_variant | ENSP00000497441.1 | ||||||
DSC2 | ENST00000682357.1 | c.202-2A>G | splice_acceptor_variant, intron_variant | ENSP00000507826.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251040Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135772
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461274Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 726976
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:10Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Pathogenic:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 23, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change affects an acceptor splice site in intron 5 of the DSC2 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 DSC2 are known to be pathogenic (PMID: 23911551). This variant is present in population databases (rs397514042, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466). ClinVar contains an entry for this variant (Variation ID: 16850). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17186466). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | This variant alters a canonical splice acceptor site in DSC2. This variant has been described previously in the heterozygous state in a patient with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466). - |
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 01, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2022 | 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: 32466575, 25390934, 33684294, 32853555, 31402444, 32665702, 23812740, 31872082, 34135346, 33087929, 29788292, 33500567, 17186466) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2023 | The c.631-2A>G intronic variant results from an A to G substitution two nucleotides before from coding exon 6 in the DSC2 gene. This variant has been detected in an individual from an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort with limited clinical detail, and in an individual reported to meet ARVC diagnostic criteria (Baskin B et al. Hum Genet, 2013 Nov;132:1245-52; Heuser A et al. Am J Hum Genet, 2006 Dec;79:1081-8). This variant has also been detected in several cohorts without known ARVC; however, clinical details were often limited (Mazzarotto F et al. Genet Med, 2021 05;23:856-864; Carruth ED et al. Circ Genom Precis Med, 2021 04;14:e003302; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51; van Rooij J et al. Genet Med, 2020 11;22:1812-1820; Roman TS et al. Am J Hum Genet, 2020 10;107:596-611; Gierman HJ et al. PLoS One, 2014 Nov;9:e112430). In RNA studies by one group, this alteration resulted in aberrant splicing due to use of a cryptic donor site resulting in a frameshift and premature truncation (Heuser A et al. Am J Hum Genet, 2006 Dec;79:1081-8). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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 likely pathogenic. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 15, 2019 | The c.631-2A>G variant in DSC2 has been reported in 2 individuals with ARVC and 1 individual with LVNC (Heuser 2006, LMM data). It was also reported in a 110-year-old individual (Gierman 2014) and in ClinVar (Variation ID: 16850). This variant has been identified in 4/111556 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence, and in vitro studies confirmed that it leads to aberrant splicing and reduced DSC2 protein levels (Heuser 2006). Splice and other loss-of-function variants in DSC2 have been reported in individuals with ARVC; however, the clinical significance of these variants is not yet fully understood. Although ARVC has primarily been described as a dominant disorder, in several reports of loss-of function variants, only those individuals with a variant on the second allele were affected, suggesting that LOF variants may either act in a recessive manner or have a much milder effect than missense variants. In summary, while there is some suspicion for a pathogenic role in the heterozygous state, the clinical significance of the c.631-2A>G variant, with regard to dominant ARVC is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PS3_Moderate. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 2023 | This variant alters the canonical splice acceptor site in intron 5 of the DSC2 gene. Computational splicing tools predict that this variant may disrupt splicing. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466, 23812740). This variant has also been identified in 4/251040 chromosomes in the general population by the Genome Aggregation Database (gnomAD), as well as in a supercentenarian (110 years or older) (PMID: 25390934). Quantitative real-time PCR in cardiac tissue biopsy of an affected individual has shown that this variant leads to aberrant splicing and reduced DSC2 protein levels (PMID: 17186466). Splice and other loss-of-function DSC2 variants have been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy. Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This variant alters the canonical splice acceptor site in intron 5 of the DSC2 gene. Computational splicing tools predict that this variant may disrupt splicing. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466, 23812740). This variant has also been identified in 4/251040 chromosomes in the general population by the Genome Aggregation Database (gnomAD), as well as in a supercentenarian (110 years or older) (PMID: 25390934). Quantitative real-time PCR in cardiac tissue biopsy of an affected individual has shown that this variant leads to aberrant splicing and reduced DSC2 protein levels (PMID: 17186466). Splice and other loss-of-function DSC2 variants have been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy. Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -27
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at