19-11237653-G-A

Position:

• chr19-11237653-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_020812.4(DOCK6):​c.1959C>T​(p.Pro653=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,597,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: DOCK6 NM_020812.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.693

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-11237653-G-A is Benign according to our data. Variant chr19-11237653-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 785608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.693 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00253 (385/152152) while in subpopulation AFR AF= 0.00892 (370/41496). AF 95% confidence interval is 0.00817. There are 0 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK6	NM_020812.4	c.1959C>T	p.Pro653=	synonymous_variant	17/48	ENST00000294618.12	NP_065863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK6	ENST00000294618.12	c.1959C>T	p.Pro653=	synonymous_variant	17/48	1	NM_020812.4	ENSP00000294618	A2

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000579 AC: 126 AN: 217622 Hom.: 0 AF XY: 0.000442 AC XY: 52 AN XY: 117594

Gnomad AFR exome AF: 0.00828

Gnomad AMR exome AF: 0.000484

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000613

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000284 AC: 411 AN: 1445422 Hom.: 0 Cov.: 35 AF XY: 0.000252 AC XY: 181 AN XY: 717118

Gnomad4 AFR exome AF: 0.00844

Gnomad4 AMR exome AF: 0.000549

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000561

Gnomad4 OTH exome AF: 0.000585

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.00238 AC XY: 177 AN XY: 74376

Gnomad4 AFR AF: 0.00892

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	DOCK6: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.0
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200269584; hg19: chr19-11348329;