rs200393834

Positions:

• chr19-11200710-G-A

Variant summary

Our verdict is Benign. Variant got -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:1 B:5
• Conservation: PhyloP100: 0.486

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 -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 id is 445617.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=1}. Variant chr19-11200710-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK6	NM_020812.4	c.5939+6C>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.5939+6C>T		splice_region_variant, intron_variant		1	NM_020812.4	ENSP00000294618.6
DOCK6	ENST00000587656.6	c.6044+6C>T		splice_region_variant, intron_variant		5		ENSP00000468638.2
DOCK6	ENST00000587734.1	c.76-1171C>T		intron_variant		5		ENSP00000468291.1
DOCK6	ENST00000586702.1	n.842+6C>T		splice_region_variant, intron_variant		2

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

GnomAD3 exomes AF: 0.00160 AC: 391 AN: 244046 Hom.: 2 AF XY: 0.00168 AC XY: 223 AN XY: 132482

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 SAS exome AF: 0.000867

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

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000813

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000630

Gnomad4 FIN exome AF: 0.000230

Gnomad4 NFE exome AF: 0.00322

Gnomad4 OTH exome AF: 0.00292

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

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	DOCK6: BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	21
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs200393834; hg19: chr19-11311386;