rs397514042

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

Scores

3
1
3
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:3

Conservation

PhyloP100: 4.28
Variant links:
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]

Genome browser will be placed here

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: {Likely_pathogenic=4, Uncertain_significance=3, Pathogenic=3}. Variant chr18-31087815-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSC2NM_024422.6 linkc.631-2A>G splice_acceptor_variant, intron_variant Intron 5 of 15 ENST00000280904.11 NP_077740.1 Q02487-1
DSC2NM_004949.5 linkc.631-2A>G splice_acceptor_variant, intron_variant Intron 5 of 16 NP_004940.1 Q02487-2
DSC2NM_001406506.1 linkc.202-2A>G splice_acceptor_variant, intron_variant Intron 5 of 15 NP_001393435.1
DSC2NM_001406507.1 linkc.202-2A>G splice_acceptor_variant, intron_variant Intron 5 of 16 NP_001393436.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSC2ENST00000280904.11 linkc.631-2A>G splice_acceptor_variant, intron_variant Intron 5 of 15 1 NM_024422.6 ENSP00000280904.6 Q02487-1
DSC2ENST00000251081.8 linkc.631-2A>G splice_acceptor_variant, intron_variant Intron 5 of 16 1 ENSP00000251081.6 Q02487-2
DSC2ENST00000648081.1 linkc.202-2A>G splice_acceptor_variant, intron_variant Intron 6 of 16 ENSP00000497441.1 A0A3B3ISU0
DSC2ENST00000682357.1 linkc.202-2A>G splice_acceptor_variant, intron_variant Intron 5 of 15 ENSP00000507826.1 A0A3B3ISU0

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251040
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135772
show subpopulations
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000274
AC:
40
AN:
1461274
Hom.:
0
Cov.:
31
AF XY:
0.0000316
AC XY:
23
AN XY:
726976
show subpopulations
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:
0.0000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000669
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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
Dec 09, 2022
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dec 23, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 09, 2025
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 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. -

-
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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
Sep 07, 2022
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: 32466575, 25390934, 33684294, 32853555, 31402444, 32665702, 23812740, 31872082, 34135346, 33087929, 29788292, 33500567, 17186466) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 01, 2021
AiLife Diagnostics, AiLife Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1
Sep 08, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Cardiomyopathy Uncertain:1
Feb 28, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Aug 15, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Dec 01, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
30
DANN
Benign
0.97
Eigen
Pathogenic
0.82
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.76
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.61
Position offset: -27
DS_AL_spliceai
0.99
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.

Other links and lift over

dbSNP: rs397514042; hg19: chr18-28667778; API