rs755069593
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The ENST00000379802.8(DSP):āc.6269A>Gā(p.Glu2090Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000379802.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.6269A>G | p.Glu2090Gly | missense_variant | 24/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.4940A>G | p.Glu1647Gly | missense_variant | 24/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.4472A>G | p.Glu1491Gly | missense_variant | 24/24 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.6269A>G | p.Glu2090Gly | missense_variant | 24/24 | 1 | NM_004415.4 | ENSP00000369129 | P2 | |
DSP | ENST00000418664.2 | c.4472A>G | p.Glu1491Gly | missense_variant | 24/24 | 1 | ENSP00000396591 | A2 | ||
DSP | ENST00000710359.1 | c.4940A>G | p.Glu1647Gly | missense_variant | 24/24 | ENSP00000518230 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251392Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135876
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727238
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152342Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74496
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 16, 2014 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data and the type of variant, we consider this variant a variant of uncertain significance. We could find no reported cases of disease with this variant. Specifically, it is not listed in ClinVar or the ARVD mutation database. PolyPhen2 and MutationTaster both predict the variant to be disease causing with scores of 0.985 and 1.000 respectively. SIFT does not predict the variant to be disease causing, though the score (0.93) is close to the cutoff (0.95). The glutamic acid at codon 2090 is completely conserved across species. It is notable that most pathogenic variants in DSP are not missense. The variant was reported online in 2 of 60431 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 22nd, 2015). Specifically, the variant was observed in 2 of 33217 European individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 22, 2024 | This missense variant replaces glutamic acid with glycine at codon 2090 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 6/251392 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
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 11, 2023 | This missense variant replaces glutamic acid with glycine at codon 2090 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has been identified in 6/251392 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. - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | Oct 18, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Identified in patients referred for cardiomyopathy genetic testing at GeneDx, although one of these probands harbored an additional cardiogenetic variant that likely contributed to the phenotype; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 234989; Landrum et al., 2016) - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PM2, PP3 - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2023 | The p.E2090G variant (also known as c.6269A>G), located in coding exon 24 of the DSP gene, results from an A to G substitution at nucleotide position 6269. The glutamic acid at codon 2090 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. 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. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at