rs794728084
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_001943.5(DSG2):c.2923delG(p.Val975fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Consequence
DSG2
NM_001943.5 frameshift
NM_001943.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.98
Genes affected
DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.129 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-31546307-TG-T is Pathogenic according to our data. Variant chr18-31546307-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199801.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.2923delG | p.Val975fs | frameshift_variant | Exon 15 of 15 | ENST00000261590.13 | NP_001934.2 | |
DSG2 | XM_047437315.1 | c.2389delG | p.Val797fs | frameshift_variant | Exon 16 of 16 | XP_047293271.1 | ||
DSG2-AS1 | NR_045216.1 | n.1346-402delC | intron_variant | Intron 3 of 5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.2923delG | p.Val975fs | frameshift_variant | Exon 15 of 15 | 1 | NM_001943.5 | ENSP00000261590.8 | ||
DSG2-AS1 | ENST00000583706.5 | n.1384-402delC | intron_variant | Intron 3 of 5 | 5 | |||||
DSG2-AS1 | ENST00000657343.1 | n.697-402delC | intron_variant | Intron 3 of 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000410 AC: 1AN: 243810Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 132006
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 20, 2024 | This sequence change creates a premature translational stop signal (p.Val975*) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs794728084, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 199801). This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 04, 2024 | - - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2023 | Has not been previously published in association with DSG2-related disease to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 144 amino acids are lost.; This variant is associated with the following publications: (PMID: 33684294) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2024 | The c.2923delG variant, located in coding exon 15 of the DSG2 gene, results from a deletion of one nucleotide at nucleotide position 2923, causing a translational frameshift with a predicted alternate stop codon (p.V975*). This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 13% of the protein. The exact functional effect of this alteration is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at