chr19-11213198-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_020812.4(DOCK6):c.4469G>A(p.Arg1490Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,612,778 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_020812.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DOCK6 | ENST00000294618.12 | c.4469G>A | p.Arg1490Gln | missense_variant | Exon 35 of 48 | 1 | NM_020812.4 | ENSP00000294618.6 | ||
DOCK6 | ENST00000587656.6 | c.4574G>A | p.Arg1525Gln | missense_variant | Exon 36 of 49 | 5 | ENSP00000468638.2 | |||
ENSG00000267082 | ENST00000588634.1 | n.538-2939C>T | intron_variant | Intron 2 of 2 | 4 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000173 AC: 43AN: 247926Hom.: 0 AF XY: 0.000156 AC XY: 21AN XY: 134760
GnomAD4 exome AF: 0.000399 AC: 582AN: 1460466Hom.: 2 Cov.: 31 AF XY: 0.000391 AC XY: 284AN XY: 726412
GnomAD4 genome AF: 0.000158 AC: 24AN: 152312Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10AN XY: 74474
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1490 of the DOCK6 protein (p.Arg1490Gln). This variant is present in population databases (rs200472954, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DOCK6-related conditions. ClinVar contains an entry for this variant (Variation ID: 202182). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
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; This variant is associated with the following publications: (PMID: 31589614) -
Adams-Oliver syndrome 2 Pathogenic:1
- -
DOCK6-related disorder Uncertain:1
The DOCK6 c.4469G>A variant is predicted to result in the amino acid substitution p.Arg1490Gln. To our knowledge, this variant has not been documented in any individuals affected with DOCK6-related Adams-Oliver syndrome type 2. It is reported in a single heterozygous individual from a carrier screening paper (Capalbo et al 2019. PubMed ID: 31589614). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at