19-11236849-C-T

Variant names:

• chr19-11236849-C-T
• rs199838752
• NM_020812.4:c.2104G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001367830.1(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 NM_001367830.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.16
• Publications: 6 publications found

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: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Adams-Oliver syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 523606.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367830.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK6	NM_020812.4	MANE Select	c.2104G>A	p.Gly702Ser	missense	Exon 19 of 48	NP_065863.2
	DOCK6	NM_001367830.1		c.2104G>A	p.Gly702Ser	missense	Exon 19 of 49	NP_001354759.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK6	ENST00000294618.12	TSL:1 MANE Select	c.2104G>A	p.Gly702Ser	missense	Exon 19 of 48	ENSP00000294618.6
	DOCK6	ENST00000587656.6	TSL:5	c.2104G>A	p.Gly702Ser	missense	Exon 19 of 49	ENSP00000468638.2
	DOCK6	ENST00000590680.5	TSL:5	c.445G>A	p.Gly149Ser	missense	Exon 5 of 11	ENSP00000467191.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152162 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.00284 AC: 455 AN: 160212 AF XY: 0.00360

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 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.: 22 Cov.: 32 AF XY: 0.00223 AC XY: 1542 AN XY: 692666

African (AFR) AF: 0.000126 AC: 4 AN: 31684

American (AMR) AF: 0.000775 AC: 28 AN: 36120

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 102 AN: 25250

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35994

South Asian (SAS) AF: 0.0118 AC: 937 AN: 79400

European-Finnish (FIN) AF: 0.00153 AC: 75 AN: 49100

Middle Eastern (MID) AF: 0.00912 AC: 52 AN: 5700

European-Non Finnish (NFE) AF: 0.00118 AC: 1273 AN: 1081764

Other (OTH) AF: 0.00232 AC: 135 AN: 58190

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74466

African (AFR) AF: 0.000385 AC: 16 AN: 41562

American (AMR) AF: 0.000719 AC: 11 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00141 Hom.: 4

Bravo AF: 0.00102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000491 AC: 2

ESP6500EA AF: 0.000994 AC: 8

ExAC AF: 0.00183 AC: 193

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Adams-Oliver syndrome 2 (1)
-	-	1	DOCK6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.093
Sift	Uncertain	0.017	D
Sift4G	Benign	0.32	T
Polyphen		0.59	P
Vest4		0.27
MVP		0.41
MPC		0.35
ClinPred		0.036	T
GERP RS		3.6
PromoterAI		-0.013	Neutral
Varity_R		0.20
gMVP		0.56
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs199838752; hg19: chr19-11347525; COSMIC: COSV52949394; COSMIC: COSV52949394;