chr19-11200710-G-A

Variant names:

• chr19-11200710-G-A
• rs200393834
• NM_020812.4:c.5939+6C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_020812.4(DOCK6):​c.5939+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,609,868 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: DOCK6 NM_020812.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008298
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.486
• Publications: 1 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-AS1 (HGNC:56684): (DOCK6 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-11200710-G-A is Benign according to our data. Variant chr19-11200710-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445617.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.5939+6C>T		splice_region intron	N/A	NP_065863.2	Q96HP0
	DOCK6	NM_001367830.1		c.6044+6C>T		splice_region intron	N/A	NP_001354759.1	K7ESB7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK6	ENST00000294618.12	TSL:1 MANE Select	c.5939+6C>T		splice_region intron	N/A	ENSP00000294618.6	Q96HP0
	DOCK6	ENST00000587656.6	TSL:5	c.6044+6C>T		splice_region intron	N/A	ENSP00000468638.2	K7ESB7
	DOCK6	ENST00000587734.1	TSL:5	c.76-1171C>T		intron	N/A	ENSP00000468291.1	K7ERK2

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00160 AC: 391 AN: 244046 AF XY: 0.00168

Gnomad AFR exome AF: 0.000265

Gnomad AMR exome AF: 0.000854

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000244

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00266 AC: 3870 AN: 1457582 Hom.: 9 Cov.: 32 AF XY: 0.00263 AC XY: 1909 AN XY: 724646

African (AFR) AF: 0.000269 AC: 9 AN: 33436

American (AMR) AF: 0.000813 AC: 36 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.000630 AC: 54 AN: 85706

European-Finnish (FIN) AF: 0.000230 AC: 12 AN: 52222

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00322 AC: 3580 AN: 1110222

Other (OTH) AF: 0.00292 AC: 176 AN: 60266

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74482

African (AFR) AF: 0.000505 AC: 21 AN: 41566

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	21
DANN	Benign	0.77
PhyloP100		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 2

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

Other links and lift over

dbSNP: rs200393834; hg19: chr19-11311386;