chr18-31546307-TG-T
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
Consequence
NM_001943.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
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
GnomAD3 exomes AF: 0.00000410 AC: 1AN: 243810Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 132006
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1
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
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Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
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not provided Uncertain:1
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at