rs369682599
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004415.4(DSP):c.8482G>A(p.Gly2828Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000745 in 1,610,202 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_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.8482G>A | p.Gly2828Ser | missense_variant | Exon 24 of 24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.7153G>A | p.Gly2385Ser | missense_variant | Exon 24 of 24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.6685G>A | p.Gly2229Ser | missense_variant | Exon 24 of 24 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.8482G>A | p.Gly2828Ser | missense_variant | Exon 24 of 24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.6685G>A | p.Gly2229Ser | missense_variant | Exon 24 of 24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.7153G>A | p.Gly2385Ser | missense_variant | Exon 24 of 24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000364 AC: 9AN: 247242Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 134128
GnomAD4 exome AF: 0.0000768 AC: 112AN: 1458106Hom.: 0 Cov.: 33 AF XY: 0.0000841 AC XY: 61AN XY: 725058
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74306
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: DSP c.8482G>A (p.Gly2828Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 247242 control chromosomes. 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.8482G>A in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 405239). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
This missense variant replaces glycine with serine at codon 2828 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with idiopathic ventricular fibrillation (PMID: 31114860). This variant has been identified in 14/278596 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. -
Cardiomyopathy Uncertain:1
This missense variant replaces glycine with serine at codon 2828 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with idiopathic ventricular fibrillation (PMID: 31114860), and in another individual who experienced sudden infant death (PMID: 37589201). This variant has been identified in 14/278596 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. -
Cardiovascular phenotype Uncertain:1
The p.G2828S variant (also known as c.8482G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 8482. The glycine at codon 2828 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
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Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at