chr18-31546667-GTC-TTA
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001943.5(DSG2):c.3281_3283delGTCinsTTA(p.GlyHis1094ValAsn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.3281_3283delGTCinsTTA | p.GlyHis1094ValAsn | missense_variant | ENST00000261590.13 | NP_001934.2 | ||
DSG2 | XM_047437315.1 | c.2747_2749delGTCinsTTA | p.GlyHis916ValAsn | missense_variant | XP_047293271.1 | |||
DSG2-AS1 | NR_045216.1 | n.1346-763_1346-761delGACinsTAA | intron_variant | Intron 3 of 5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.3281_3283delGTCinsTTA | p.GlyHis1094ValAsn | missense_variant | 1 | NM_001943.5 | ENSP00000261590.8 | |||
DSG2-AS1 | ENST00000583706.5 | n.1384-763_1384-761delGACinsTAA | intron_variant | Intron 3 of 5 | 5 | |||||
DSG2-AS1 | ENST00000657343.1 | n.697-763_697-761delGACinsTAA | intron_variant | Intron 3 of 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: DSG2 c.3281_3283delinsTTA (p.Gly1094_His1095delinsValAsn) results in an in-frame deletion-insertion that is predicted to delete two amino acids and also cause insert in two amino acids in the last exon of the protein. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 280622 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3281_3283delinsTTA in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
The Gly1094_His1095delinsValAsn variant in DSG2 has not been previously reported in individuals with cardiomyopathy. This variant is equivalent to 2 missense va riants (Gly1094Val and His1095Asn), though because they occur on the same copy o f the gene (in cis), they are described as above. Each missense variant has been identified in 3/3969 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs144313973 and rs140193292), though it is assumed that these actually represent this variant (dbSNP rs386802 145). This variant is a deletion of 2 amino acids at position 1094 and 1095 and an insertion of two different amino acids at these positions and is not predicte d to alter the protein reading-frame. While the affected amino acids are not wel l conserved, it is unclear if this variant will impact the protein. In summary, the clinical significance of the Gly1094_His1095delinsValAsn variant is uncertai n. -
Cardiomyopathy Benign:2
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Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Uncertain:1
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Arrhythmogenic right ventricular dysplasia 10 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at