rs372751467

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020812.4(DOCK6):​c.3562C>T​(p.Gln1188*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,612,982 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DOCK6
NM_020812.4 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.30
Variant links:
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]

Genome browser will be placed here

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 19-11217380-G-A is Pathogenic according to our data. Variant chr19-11217380-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 499360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOCK6NM_020812.4 linkuse as main transcriptc.3562C>T p.Gln1188* stop_gained 29/48 ENST00000294618.12 NP_065863.2 Q96HP0B7Z9U8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOCK6ENST00000294618.12 linkuse as main transcriptc.3562C>T p.Gln1188* stop_gained 29/481 NM_020812.4 ENSP00000294618.6 Q96HP0
DOCK6ENST00000587656.6 linkuse as main transcriptc.3667C>T p.Gln1223* stop_gained 30/495 ENSP00000468638.2 K7ESB7

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152202
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000284
AC:
7
AN:
246826
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134270
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000584
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000448
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1460780
Hom.:
0
Cov.:
33
AF XY:
0.0000138
AC XY:
10
AN XY:
726596
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000673
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152202
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000744
Hom.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000359
AC:
3
ExAC
AF:
0.0000496
AC:
6

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023This sequence change creates a premature translational stop signal (p.Gln1188*) 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 (rs372751467, gnomAD 0.006%). 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: 499360). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 21, 2016- -
Adams-Oliver syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Laboratory, M Health Fairview: University of MinnesotaAug 14, 2018- -
DOCK6-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 21, 2023The DOCK6 c.3562C>T variant is predicted to result in premature protein termination (p.Gln1188*). To our knowledge, this variant has not been reported in a patient with a DOCK6 related disorder. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11328056-G-A). Nonsense variants in DOCK6 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
45
DANN
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.83
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372751467; hg19: chr19-11328056; API