rs148502872

chr5-170067575-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM2 PP2 BP4_Strong BP6_Moderate BS1

The NM_004946.3(DOCK2):c.4533G>T(p.Met1511Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.03

Genes affected

DOCK2 (HGNC:2988): (dedicator of cytokinesis 2) The protein encoded by this gene belongs to the CDM protein family. It is specifically expressed in hematopoietic cells and is predominantly expressed in peripheral blood leukocytes. The protein is involved in remodeling of the actin cytoskeleton required for lymphocyte migration in response to chemokine signaling. It activates members of the Rho family of GTPases, for example RAC1 and RAC2, by acting as a guanine nucleotide exchange factor (GEF) to exchange bound GDP for free GTP. Mutations in this gene result in immunodeficiency 40 (IMD40), a combined form of immunodeficiency that affects T cell number and function, also with variable defects in B cell and NK cell function. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DOCK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.010901779).
• BP6: Variant 5-170067575-G-T is Benign according to our data. Variant chr5-170067575-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 542638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00109 (166/152310) while in subpopulation AFR AF= 0.00387 (161/41552). AF 95% confidence interval is 0.00339. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.4533G>T	p.Met1511Ile	missense_variant	45/52	ENST00000520908.7
DOCK2	NR_156756.1	n.4636G>T		non_coding_transcript_exon_variant	46/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.4533G>T	p.Met1511Ile	missense_variant	45/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000262 AC: 66 AN: 251430 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135882

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.000434

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461874 Hom.: 0 Cov.: 30 AF XY: 0.0000756 AC XY: 55 AN XY: 727240

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74480

Gnomad4 AFR AF: 0.00387

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.00111

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000296 AC: 36

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DOCK2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.51	D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.083
Sift	Benign	0.10	T;.
Sift4G	Benign	0.15	T;.
Polyphen		0.18	B;B
Vest4		0.40
MutPred		0.45		Gain of ubiquitination at K1508 (P = 0.1106);Gain of ubiquitination at K1508 (P = 0.1106);
MVP		0.35
MPC		0.62
ClinPred		0.013	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.39
gMVP		0.57

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: rs148502872; hg19: chr5-169494579;