19-11237532-C-T

Position:

• chr19-11237532-C-T

Variant summary

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

The ENST00000294618.12(DOCK6):​c.1997G>A​(p.Arg666His) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,612,110 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R666C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 29)
  • Exomes 𝑓: 0.00097 (20 hom.)
• Consequence: DOCK6 ENST00000294618.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.99

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]

ANGPTL8 (HGNC:24933): (angiopoietin like 8) Predicted to enable hormone activity. Involved in regulation of lipid metabolic process and triglyceride homeostasis. Acts upstream of or within positive regulation of protein processing and regulation of lipoprotein metabolic process. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

DOCK6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-11237532-C-T is Benign according to our data. Variant chr19-11237532-C-T is described in ClinVar as [Benign]. Clinvar id is 719828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00679 (1025/150920) while in subpopulation AFR AF= 0.0239 (979/41016). AF 95% confidence interval is 0.0226. There are 13 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK6	NM_020812.4	c.1997G>A	p.Arg666His	missense_variant	18/48	ENST00000294618.12	NP_065863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK6	ENST00000294618.12	c.1997G>A	p.Arg666His	missense_variant	18/48	1	NM_020812.4	ENSP00000294618.6

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1018 AN: 150802 Hom.: 12 Cov.: 29

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000420

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.00339

GnomAD3 exomes AF: 0.00192 AC: 476 AN: 248410 Hom.: 9 AF XY: 0.00157 AC XY: 212 AN XY: 134952

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.000957

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000973 AC: 1422 AN: 1461190 Hom.: 20 Cov.: 36 AF XY: 0.000902 AC XY: 656 AN XY: 726872

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00679 AC: 1025 AN: 150920 Hom.: 13 Cov.: 29 AF XY: 0.00643 AC XY: 474 AN XY: 73682

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.00198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000421

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.00336

Alfa AF: 0.00310 Hom.: 6

Bravo AF: 0.00817

ESP6500AA AF: 0.0243 AC: 94

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.00235 AC: 284

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.095
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.70	P
Vest4		0.33
MVP		0.30
MPC		0.26
ClinPred		0.086	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		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: rs114281937; hg19: chr19-11348208;