10-126999453-T-C

Variant names:

• chr10-126999453-T-C
• rs2275540
• NM_001290223.2:c.849+18T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001290223.2(DOCK1):​c.849+18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,604,738 control chromosomes in the GnomAD database, including 38,128 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (3626 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34502 hom.)
• Consequence: DOCK1 NM_001290223.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 12 publications found

Genes affected

DOCK1 (HGNC:2987): (dedicator of cytokinesis 1) This gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins act as guanine nucleotide exchange factors for small Rho family G proteins. The encoded protein regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. Overexpression of this gene has also been associated with certain cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ENSG00000223528 (HGNC:58348):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK1	NM_001290223.2	c.849+18T>C		intron_variant	Intron 9 of 51	ENST00000623213.2	NP_001277152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK1	ENST00000623213.2	c.849+18T>C		intron_variant	Intron 9 of 51	1	NM_001290223.2	ENSP00000485033.1
DOCK1	ENST00000280333.9	c.849+18T>C		intron_variant	Intron 9 of 51	1		ENSP00000280333.6
ENSG00000223528	ENST00000627944.1	n.215+823A>G		intron_variant	Intron 2 of 2	5
ENSG00000223528	ENST00000629917.1	n.201-62A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33031 AN: 151988 Hom.: 3628 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.240

GnomAD2 exomes AF: 0.235 AC: 57415 AN: 244438 AF XY: 0.228

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.327

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.214 AC: 310700 AN: 1452632 Hom.: 34502 Cov.: 28 AF XY: 0.212 AC XY: 153417 AN XY: 722722

African (AFR) AF: 0.209 AC: 6976 AN: 33322

American (AMR) AF: 0.310 AC: 13716 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4596 AN: 25894

East Asian (EAS) AF: 0.339 AC: 13455 AN: 39636

South Asian (SAS) AF: 0.178 AC: 15165 AN: 85402

European-Finnish (FIN) AF: 0.224 AC: 11949 AN: 53288

Middle Eastern (MID) AF: 0.206 AC: 1186 AN: 5754

European-Non Finnish (NFE) AF: 0.209 AC: 230649 AN: 1105042

Other (OTH) AF: 0.217 AC: 13008 AN: 60076

GnomAD4 genome AF: 0.217 AC: 33048 AN: 152106 Hom.: 3626 Cov.: 32 AF XY: 0.218 AC XY: 16212 AN XY: 74342

African (AFR) AF: 0.210 AC: 8713 AN: 41482

American (AMR) AF: 0.259 AC: 3954 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 585 AN: 3472

East Asian (EAS) AF: 0.335 AC: 1726 AN: 5156

South Asian (SAS) AF: 0.188 AC: 907 AN: 4822

European-Finnish (FIN) AF: 0.212 AC: 2239 AN: 10576

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14269 AN: 68000

Other (OTH) AF: 0.240 AC: 506 AN: 2104

Alfa AF: 0.209 Hom.: 4818

Bravo AF: 0.224

Asia WGS AF: 0.278 AC: 967 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.018
DANN	Benign	0.39
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2275540; hg19: chr10-128797717; COSMIC: COSV54741267; COSMIC: COSV54741267;