19-11252192-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020812.4(DOCK6):c.434G>A(p.Arg145Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000783 in 1,582,050 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0041 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 4 hom. )

Consequence

DOCK6
NM_020812.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.99

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Adams-Oliver syndrome
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Adams-Oliver syndrome 2
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

DOCK6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007884562).

BP6

Variant 19-11252192-C-T is Benign according to our data. Variant chr19-11252192-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0041 (624/152264) while in subpopulation AFR AF = 0.0143 (592/41542). AF 95% confidence interval is 0.0133. There are 3 homozygotes in GnomAd4. There are 297 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020812.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK6	NM_020812.4	MANE Select	c.434G>A	p.Arg145Gln	missense	Exon 5 of 48	NP_065863.2	Q96HP0
	DOCK6	NM_001367830.1		c.434G>A	p.Arg145Gln	missense	Exon 5 of 49	NP_001354759.1	K7ESB7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK6	ENST00000294618.12	TSL:1 MANE Select	c.434G>A	p.Arg145Gln	missense	Exon 5 of 48	ENSP00000294618.6	Q96HP0
DOCK6	ENST00000587656.6	TSL:5	c.434G>A	p.Arg145Gln	missense	Exon 5 of 49	ENSP00000468638.2	K7ESB7
DOCK6	ENST00000585609.1	TSL:2	n.940G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

622

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00110

AC:

217

AN:

196994

AF XY:

0.000849

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.000959

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000139

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000582

GnomAD4 exome

AF:

0.000430

AC:

615

AN:

1429786

Hom.:

Cov.:

AF XY:

0.000384

AC XY:

272

AN XY:

708064

show subpopulations

African (AFR)

AF:

0.0149

AC:

491

AN:

32866

American (AMR)

AF:

0.00110

AC:

AN:

39132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25496

East Asian (EAS)

AF:

0.0000524

AC:

AN:

38184

South Asian (SAS)

AF:

0.000208

AC:

AN:

81774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51204

Middle Eastern (MID)

AF:

0.000698

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00000456

AC:

AN:

1096108

Other (OTH)

AF:

0.000894

AC:

AN:

59292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00410

AC:

624

AN:

152264

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

297

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0143

AC:

592

AN:

41542

American (AMR)

AF:

0.00131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00470

ESP6500AA

AF:

0.0149

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00112

AC:

135

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

DOCK6-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

Eigen

Benign

0.18

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0079

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

3.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

REVEL

Benign

0.062

Sift

Benign

0.29

Sift4G

Benign

0.44

Polyphen

0.94

Vest4

0.30

MVP

0.51

MPC

0.23

ClinPred

0.019

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.14

gMVP

0.34

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over