rs201363937
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_024422.6(DSC2):c.267G>A(p.Ser89=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
DSC2
NM_024422.6 synonymous
NM_024422.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.776
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP6
?
Variant 18-31092188-C-T is Benign according to our data. Variant chr18-31092188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46185.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.267G>A | p.Ser89= | synonymous_variant | 3/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.267G>A | p.Ser89= | synonymous_variant | 3/17 | ||
DSC2 | NM_001406506.1 | c.-163G>A | 5_prime_UTR_variant | 3/16 | |||
DSC2 | NM_001406507.1 | c.-163G>A | 5_prime_UTR_variant | 3/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.267G>A | p.Ser89= | synonymous_variant | 3/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.267G>A | p.Ser89= | synonymous_variant | 3/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.-200G>A | 5_prime_UTR_variant | 3/17 | |||||
DSC2 | ENST00000682357.1 | c.-163G>A | 5_prime_UTR_variant | 3/16 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250864Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135590
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461388Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726992
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74268
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2022 | The c.267G>A variant (also known as p.S89S), located in coding exon 3 of the DSC2 gene, results from a G to A substitution at nucleotide position 267. This nucleotide substitution does not change the amino acid at codon 89. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 | Nov 16, 2023 | This variant is located in the DSC2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 2/250864 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Ser89Ser in Exon 03 of DSC2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence. It has been identified in 1/7018 European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS;). - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at