chr9-128947012-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014908.4(DOLK):c.292C>T(p.Arg98Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R98Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_014908.4 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 | UniProt |
---|---|---|---|---|---|---|---|
DOLK | NM_014908.4 | c.292C>T | p.Arg98Trp | missense_variant | 1/1 | ENST00000372586.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOLK | ENST00000372586.4 | c.292C>T | p.Arg98Trp | missense_variant | 1/1 | NM_014908.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248786Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134706
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1458846Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 725850
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74272
ClinVar
Submissions by phenotype
DK1-congenital disorder of glycosylation Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2022 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DOLK protein function. ClinVar contains an entry for this variant (Variation ID: 568082). This variant has not been reported in the literature in individuals affected with DOLK-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 98 of the DOLK protein (p.Arg98Trp). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 15, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2021 | The p.R98W variant (also known as c.292C>T), located in coding exon 1 of the DOLK gene, results from a C to T substitution at nucleotide position 292. The arginine at codon 98 is replaced by tryptophan, an amino acid with dissimilar 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at