NM_020812.4:c.3913C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_020812.4(DOCK6):c.3913C>T(p.Arg1305Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00972 in 1,613,744 control chromosomes in the GnomAD database, including 101 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. R1305H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0078 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 94 hom. )

Consequence

DOCK6
NM_020812.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.640

Publications

7 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 links:

DOCK6-AS1 (HGNC:56684): (DOCK6 antisense RNA 1)

DOCK6-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 19-11215909-G-A is Benign according to our data. Variant chr19-11215909-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00782 (1190/152134) while in subpopulation NFE AF = 0.0109 (740/68014). AF 95% confidence interval is 0.0102. There are 7 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DOCK6	NM_020812.4	MANE Select	c.3913C>T	p.Arg1305Cys	missense	Exon 31 of 48	NP_065863.2
DOCK6	NM_001367830.1		c.4018C>T	p.Arg1340Cys	missense	Exon 32 of 49	NP_001354759.1
DOCK6-AS1	NR_134909.1		n.538-228G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DOCK6	ENST00000294618.12	TSL:1 MANE Select	c.3913C>T	p.Arg1305Cys	missense	Exon 31 of 48	ENSP00000294618.6
DOCK6	ENST00000587656.6	TSL:5	c.4018C>T	p.Arg1340Cys	missense	Exon 32 of 49	ENSP00000468638.2
DOCK6	ENST00000588429.1	TSL:4	n.268C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00783

AC:

1190

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00581

Gnomad FIN

AF:

0.0251

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.00672

GnomAD2 exomes

AF:

0.00846

AC:

2109

AN:

249286

AF XY:

0.00861

show subpopulations

Gnomad AFR exome

AF:

0.000710

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0237

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00578

GnomAD4 exome

AF:

0.00992

AC:

14496

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00989

AC XY:

7190

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33480

American (AMR)

AF:

0.00291

AC:

130

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00806

AC:

695

AN:

86256

European-Finnish (FIN)

AF:

0.0239

AC:

1274

AN:

53364

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0106

AC:

11836

AN:

1111822

Other (OTH)

AF:

0.00747

AC:

451

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

794

1588

2382

3176

3970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

448

896

1344

1792

2240

<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:

0.00782

AC:

1190

AN:

152134

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

614

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

41506

American (AMR)

AF:

0.00426

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00582

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0251

AC:

266

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

740

AN:

68014

Other (OTH)

AF:

0.00665

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00899

Hom.:

Bravo

AF:

0.00582

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.000520

AC:

ESP6500EA

AF:

0.00998

AC:

ExAC

AF:

0.00833

AC:

1007

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00834

EpiControl

AF:

0.00948

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Adams-Oliver syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

0.032

Eigen_PC

Benign

0.021

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.8

PhyloP100

0.64

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.21

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.90

Vest4

0.93

MVP

0.37

MPC

0.81

ClinPred

0.054

GERP RS

2.5

Varity_R

0.56

gMVP

0.51

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: -11

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