NM_001290223.2:c.211A>G

Variant names:

• chr10-126981957-A-G
• rs199845959
• NM_001290223.2:c.211A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001290223.2(DOCK1):​c.211A>G​(p.Ile71Val) variant causes a missense change. The variant allele was found at a frequency of 0.000778 in 1,613,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: DOCK1 NM_001290223.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49
• Publications: 1 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028178483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK1	NM_001290223.2	c.211A>G	p.Ile71Val	missense_variant	Exon 4 of 52	ENST00000623213.2	NP_001277152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK1	ENST00000623213.2	c.211A>G	p.Ile71Val	missense_variant	Exon 4 of 52	1	NM_001290223.2	ENSP00000485033.1
DOCK1	ENST00000280333.9	c.211A>G	p.Ile71Val	missense_variant	Exon 4 of 52	1		ENSP00000280333.6

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000486 AC: 121 AN: 248910 AF XY: 0.000533

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000930

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000809 AC: 1182 AN: 1461472 Hom.: 0 Cov.: 31 AF XY: 0.000838 AC XY: 609 AN XY: 727002

African (AFR) AF: 0.000299 AC: 10 AN: 33466

American (AMR) AF: 0.000246 AC: 11 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00102 AC: 1134 AN: 1111796

Other (OTH) AF: 0.000414 AC: 25 AN: 60362

GnomAD4 genome AF: 0.000487 AC: 74 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74236

African (AFR) AF: 0.000339 AC: 14 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000541 AC: 2

ESP6500EA AF: 0.000489 AC: 4

ExAC AF: 0.000637 AC: 77

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211A>G (p.I71V) alteration is located in exon 4 (coding exon 4) of the DOCK1 gene. This alteration results from a A to G substitution at nucleotide position 211, causing the isoleucine (I) at amino acid position 71 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.060	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.76	N;.
PhyloP100		5.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.14	N;.
REVEL	Benign	0.10
Sift	Benign	0.65	T;.
Sift4G	Benign	0.72	T;T
Polyphen		0.0	B;.
Vest4		0.23
MVP		0.54
MPC		0.20
ClinPred		0.020	T
GERP RS		4.9
Varity_R		0.089
gMVP		0.22
Mutation Taster		=97/3	polymorphism

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: rs199845959; hg19: chr10-128780221;