rs145873210

chr5-170042092-C-T

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.3836C>T(p.Thr1279Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. T1279T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.799

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=0.014049262).
• BP6: Variant 5-170042092-C-T is Benign according to our data. Variant chr5-170042092-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542633.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 = 0.000617 (94/152240) while in subpopulation AFR AF= 0.00176 (73/41536). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 56 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.3836C>T	p.Thr1279Met	missense_variant	38/52	ENST00000520908.7
DOCK2	NR_156756.1	n.3939C>T		non_coding_transcript_exon_variant	39/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.3836C>T	p.Thr1279Met	missense_variant	38/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000244 AC: 61 AN: 250154 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135176

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000928

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1461108 Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77 AN XY: 726822

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000832

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74432

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000241 Hom.: 0

Bravo AF: 0.000922

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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 29, 2024

- -

DOCK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2023

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	0.070
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.085
Sift	Benign	0.052	T;.
Sift4G	Benign	0.10	T;.
Polyphen		0.83	P;P
Vest4		0.14
MVP		0.78
MPC		0.55
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.079
gMVP		0.21

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: rs145873210; hg19: chr5-169469096; COSMIC: COSV56944791; COSMIC: COSV56944791;