NM_001943.5:c.3061_3062delAG
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001943.5(DSG2):c.3061_3062delAG(p.Ser1021LeufsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001943.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.3061_3062delAG | p.Ser1021LeufsTer16 | frameshift_variant | Exon 15 of 15 | ENST00000261590.13 | NP_001934.2 | |
DSG2 | XM_047437315.1 | c.2527_2528delAG | p.Ser843LeufsTer16 | frameshift_variant | Exon 16 of 16 | XP_047293271.1 | ||
DSG2-AS1 | NR_045216.1 | n.1346-536_1346-535delCT | intron_variant | Intron 3 of 5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.3061_3062delAG | p.Ser1021LeufsTer16 | frameshift_variant | Exon 15 of 15 | 1 | NM_001943.5 | ENSP00000261590.8 | ||
DSG2-AS1 | ENST00000583706.5 | n.1384-536_1384-535delCT | intron_variant | Intron 3 of 5 | 5 | |||||
DSG2-AS1 | ENST00000657343.1 | n.697-536_697-535delCT | intron_variant | Intron 3 of 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135304
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461866Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727234
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
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Arrhythmogenic right ventricular dysplasia 10 Uncertain:1
This sequence change creates a premature translational stop signal (p.Ser1021Leufs*16) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs397516706, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 23810883, 23812740, 31847883). ClinVar contains an entry for this variant (Variation ID: 44310). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Gly1083Ser) have been observed in individuals with DSG2-related conditions (PMID: 21636032). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
The c.3061_3062delAG variant, located in coding exon 15 of the DSG2 gene, results from a deletion of two nucleotides at nucleotide positions 3061 to 3062, causing a translational frameshift with a predicted alternate stop codon (p.S1021Lfs*16). This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 8% of the protein. The exact functional effect of this alteration is unknown. This variant has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts; however, clinical details were limited, and at least one case had an additional cardiac variant detected (Baskin B et al. Hum. Genet., 2013 Nov;132:1245-52; Perrin MJ et al. J. Am. Coll. Cardiol., 2013 Nov;62:1772-9; Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at