rs3745682

Positions:

• chr19-11202580-G-A
• chr19-11202580-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020812.4(DOCK6):​c.5361+4C>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 0.402 in 1,613,742 control chromosomes in the GnomAD database, including 132,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10249 hom., cov: 32)
  • Exomes 𝑓: 0.41 (121875 hom.)
• Consequence: DOCK6 NM_020812.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.20

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-11202580-G-A is Benign according to our data. Variant chr19-11202580-G-A is described in ClinVar as [Benign]. Clinvar id is 261358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11202580-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK6	NM_020812.4	c.5361+4C>T		splice_region_variant, intron_variant		ENST00000294618.12	NP_065863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK6	ENST00000294618.12	c.5361+4C>T		splice_region_variant, intron_variant		1	NM_020812.4	ENSP00000294618.6
DOCK6	ENST00000587656.6	c.5466+4C>T		splice_region_variant, intron_variant		5		ENSP00000468638.2
DOCK6	ENST00000588666.1	c.309+4C>T		splice_region_variant, intron_variant		5		ENSP00000467231.1
DOCK6	ENST00000586702.1	n.168C>T		non_coding_transcript_exon_variant	2/7	2

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54543 AN: 151988 Hom.: 10249 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.394 AC: 98152 AN: 248936 Hom.: 19868 AF XY: 0.401 AC XY: 54247 AN XY: 135136

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.367

Gnomad SAS exome AF: 0.468

Gnomad FIN exome AF: 0.461

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.406 AC: 594037 AN: 1461636 Hom.: 121875 Cov.: 76 AF XY: 0.409 AC XY: 297103 AN XY: 727102

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.373

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.460

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.403

GnomAD4 genome AF: 0.359 AC: 54563 AN: 152106 Hom.: 10249 Cov.: 32 AF XY: 0.363 AC XY: 26937 AN XY: 74302

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.374

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.465

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.357

Alfa AF: 0.380 Hom.: 18414

Bravo AF: 0.346

Asia WGS AF: 0.421 AC: 1458 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.393

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Adams-Oliver syndrome 2 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.17
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs3745682; hg19: chr19-11313256; COSMIC: COSV53912511; COSMIC: COSV53912511;