rs141501849

Positions:

• chr5-169803090-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM2 PP2 BP4_Strong BP6_Very_Strong BS1

The NM_004946.3(DOCK2):​c.2587A>G​(p.Lys863Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.31

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 -13 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=0.015455216).
• BP6: Variant 5-169803090-A-G is Benign according to our data. Variant chr5-169803090-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 542631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000945 (144/152328) while in subpopulation AFR AF= 0.00303 (126/41572). AF 95% confidence interval is 0.0026. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.2587A>G	p.Lys863Glu	missense_variant	26/52	ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.2587A>G	p.Lys863Glu	missense_variant	26/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.000939 AC: 143 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251164 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135730

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114 AN XY: 727234

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.000335

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: 0.0000908

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000945 AC: 144 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74494

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.000854

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DOCK2 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

- -

DOCK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T;T;.;T
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.63	N;.;.;N
REVEL	Benign	0.15
Sift	Benign	0.44	T;.;.;T
Sift4G	Benign	0.35	T;.;T;T
Polyphen		0.39	B;B;.;.
Vest4		0.45
MVP		0.64
MPC		0.73
ClinPred		0.021	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.17

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: rs141501849; hg19: chr5-169230094; COSMIC: COSV105073835;