6-56640044-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_001374736.1(DST):c.2504G>A(p.Arg835His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,982 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R835C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001374736.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DST | NM_001374736.1 | c.2504G>A | p.Arg835His | missense_variant | 19/104 | ENST00000680361.1 | |
DST | NM_001723.7 | c.893G>A | p.Arg298His | missense_variant | 5/24 | ENST00000370765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DST | ENST00000680361.1 | c.2504G>A | p.Arg835His | missense_variant | 19/104 | NM_001374736.1 | |||
DST | ENST00000370765.11 | c.893G>A | p.Arg298His | missense_variant | 5/24 | 1 | NM_001723.7 |
Frequencies
GnomAD3 genomes ? AF: 0.000624 AC: 95AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000683 AC: 171AN: 250392Hom.: 0 AF XY: 0.000686 AC XY: 93AN XY: 135656
GnomAD4 exome AF: 0.00127 AC: 1855AN: 1461720Hom.: 2 Cov.: 33 AF XY: 0.00124 AC XY: 902AN XY: 727162
GnomAD4 genome ? AF: 0.000624 AC: 95AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43AN XY: 74464
ClinVar
Submissions by phenotype
Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 298 of the DST protein (p.Arg298His). This variant is present in population databases (rs41267671, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DST-related conditions. ClinVar contains an entry for this variant (Variation ID: 357614). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2021 | The p.R802H variant (also known as c.2405G>A), located in coding exon 18 of the DST gene, results from a G to A substitution at nucleotide position 2405. The arginine at codon 802 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary sensory and autonomic neuropathy type 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at