rs568049240
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020812.4(DOCK6):c.4480G>T(p.Glu1494*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,612,000 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
DOCK6
NM_020812.4 stop_gained
NM_020812.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.81
Genes affected
DOCK6 (HGNC:19189): (dedicator of cytokinesis 6) This gene encodes a member of the dedicator of cytokinesis (DOCK) family of atypical guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with small GTPases and are components of intracellular signaling networks. The encoded protein is a group C DOCK protein and plays a role in actin cytoskeletal reorganization by activating the Rho GTPases Cdc42 and Rac1. Mutations in this gene are associated with Adams-Oliver syndrome 2. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11213187-C-A is Pathogenic according to our data. Variant chr19-11213187-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 522048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11213187-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DOCK6 | NM_020812.4 | c.4480G>T | p.Glu1494* | stop_gained | 35/48 | ENST00000294618.12 | NP_065863.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DOCK6 | ENST00000294618.12 | c.4480G>T | p.Glu1494* | stop_gained | 35/48 | 1 | NM_020812.4 | ENSP00000294618.6 | ||
DOCK6 | ENST00000587656.6 | c.4585G>T | p.Glu1529* | stop_gained | 36/49 | 5 | ENSP00000468638.2 | |||
ENSG00000267082 | ENST00000588634.1 | n.538-2950C>A | intron_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152202Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000727 AC: 18AN: 247732Hom.: 0 AF XY: 0.0000446 AC XY: 6AN XY: 134678
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GnomAD4 exome AF: 0.0000329 AC: 48AN: 1459798Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 20AN XY: 725914
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GnomAD4 genome AF: 0.0000657 AC: 10AN: 152202Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74344
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Glu1494*) in the DOCK6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DOCK6 are known to be pathogenic (PMID: 21820096, 25824905). This variant is present in population databases (rs568049240, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Adams-Olive syndrome (PMID: 25091416, 28884918). ClinVar contains an entry for this variant (Variation ID: 522048). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at