rs112911897

Positions:

• chr19-11215909-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.640

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 445548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11215909-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK6	NM_020812.4	c.3913C>T	p.Arg1305Cys	missense_variant	31/48	ENST00000294618.12
LOC105372273	NR_134909.1	n.538-228G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK6	ENST00000294618.12	c.3913C>T	p.Arg1305Cys	missense_variant	31/48	1	NM_020812.4	A2
	ENST00000588634.1	n.538-228G>A		intron_variant, non_coding_transcript_variant		4
DOCK6	ENST00000587656.6	c.4018C>T	p.Arg1340Cys	missense_variant	32/49	5		P3
DOCK6	ENST00000588429.1	n.268C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.00783 AC: 1190 AN: 152016 Hom.: 7 Cov.: 32

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

GnomAD3 exomes AF: 0.00846 AC: 2109 AN: 249286 Hom.: 17 AF XY: 0.00861 AC XY: 1164 AN XY: 135248

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 SAS exome AF: 0.00761

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.: 94 Cov.: 30 AF XY: 0.00989 AC XY: 7190 AN XY: 727076

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00806

Gnomad4 FIN exome AF: 0.0239

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00747

GnomAD4 genome AF: 0.00782 AC: 1190 AN: 152134 Hom.: 7 Cov.: 32 AF XY: 0.00826 AC XY: 614 AN XY: 74358

Gnomad4 AFR AF: 0.00169

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00582

Gnomad4 FIN AF: 0.0251

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00931 Hom.: 14

Bravo AF: 0.00582

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.000520 AC: 2

ESP6500EA AF: 0.00998 AC: 82

ExAC AF: 0.00833 AC: 1007

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00834

EpiControl AF: 0.00948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

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, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DOCK6: BS1, BS2 -

Adams-Oliver syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.90	P
Vest4		0.93
MVP		0.37
MPC		0.81
ClinPred		0.054	T
GERP RS		2.5
Varity_R		0.56
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs112911897; hg19: chr19-11326585; COSMIC: COSV105133215; COSMIC: COSV105133215;