19-11200312-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_020812.4(DOCK6):c.6097C>T(p.Leu2033Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,563,594 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L2033L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: DOCK6 NM_020812.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 4.89

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070097446).
• BP6: Variant 19-11200312-G-A is Benign according to our data. Variant chr19-11200312-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 585145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000108 (152/1411276) while in subpopulation EAS AF= 0.0039 (144/36934). AF 95% confidence interval is 0.00338. There are 1 homozygotes in gnomad4_exome. There are 78 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK6	NM_020812.4	c.6097C>T	p.Leu2033Phe	missense_variant	47/48	ENST00000294618.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK6	ENST00000294618.12	c.6097C>T	p.Leu2033Phe	missense_variant	47/48	1	NM_020812.4	A2
DOCK6	ENST00000587656.6	c.6202C>T	p.Leu2068Phe	missense_variant	48/49	5		P3
DOCK6	ENST00000587734.1	c.76-773C>T		intron_variant		5
DOCK6	ENST00000586702.1	n.1000C>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000250 AC: 43 AN: 172336 Hom.: 0 AF XY: 0.000227 AC XY: 21 AN XY: 92382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000764

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000108 AC: 152 AN: 1411276 Hom.: 1 Cov.: 32 AF XY: 0.000112 AC XY: 78 AN XY: 697370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00390

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000368

Gnomad4 OTH exome AF: 0.0000513

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000106

ExAC AF: 0.000228 AC: 27

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

- -

Adams-Oliver syndrome 2 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	17
Dann	Benign	0.89
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.97	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.058
Sift	Benign	0.72	T
Sift4G	Benign	0.73	T
Polyphen		0.0010	B
Vest4		0.098
MutPred		0.14		Gain of methylation at R2034 (P = 0.0856);
MVP		0.22
MPC		0.20
ClinPred		0.054	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.069
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs556988328; hg19: chr19-11310988;