19-11236849-C-T

Position:

chr19-11236849-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000294618.12(DOCK6):c.2104G>A(p.Gly702Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,555,482 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 22 hom. )

Consequence

DOCK6
ENST00000294618.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.16

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]

DOCK6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00919348).

BP6

Variant 19-11236849-C-T is Benign according to our data. Variant chr19-11236849-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523606.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0013 (198/152280) while in subpopulation SAS AF= 0.00869 (42/4832). AF 95% confidence interval is 0.00661. There are 1 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK6	NM_020812.4 linkuse as main transcript	c.2104G>A	p.Gly702Ser	missense_variant	19/48	ENST00000294618.12	NP_065863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DOCK6	ENST00000294618.12 linkuse as main transcript	c.2104G>A	p.Gly702Ser	missense_variant	19/48	1	NM_020812.4	ENSP00000294618	A2
DOCK6	ENST00000587656.6 linkuse as main transcript	c.2104G>A	p.Gly702Ser	missense_variant	19/49	5		ENSP00000468638	P3
DOCK6	ENST00000590680.5 linkuse as main transcript	c.448G>A	p.Gly150Ser	missense_variant	5/11	5		ENSP00000467191
DOCK6	ENST00000591750.1 linkuse as main transcript	n.2073G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

197

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00848

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00284

AC:

455

AN:

160212

Hom.:

AF XY:

0.00360

AC XY:

307

AN XY:

85186

show subpopulations

Gnomad AFR exome

AF:

0.000361

Gnomad AMR exome

AF:

0.000678

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0114

Gnomad FIN exome

AF:

0.00169

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.00203

GnomAD4 exome

AF:

0.00186

AC:

2607

AN:

1403202

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

1542

AN XY:

692666

show subpopulations

Gnomad4 AFR exome

AF:

0.000126

Gnomad4 AMR exome

AF:

0.000775

Gnomad4 ASJ exome

AF:

0.00404

Gnomad4 EAS exome

AF:

0.0000278

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.00153

Gnomad4 NFE exome

AF:

0.00118

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152280

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00869

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000491

AC:

ESP6500EA

AF:

0.000994

AC:

ExAC

AF:

0.00183

AC:

193

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	DOCK6: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -

Adams-Oliver syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Centre of Medical Genetics, University of Antwerp

Dec 01, 2017

- -

DOCK6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0092

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.78

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.093

Sift

Uncertain

0.017

Sift4G

Benign

0.32

Polyphen

0.59

Vest4

0.27

MVP

0.41

MPC

0.35

ClinPred

0.036

GERP RS

3.6

Varity_R

0.20

gMVP

0.56

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over