rs199698060

chr5-170079145-G-Achr5-170079145-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BS1_Supporting

The NM_004946.3(DOCK2):c.5165G>A(p.Arg1722Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000648 in 1,612,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R1722R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: DOCK2 NM_004946.3 missense, splice_region
• Scores: Splicing: ADA: 0.8942
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.10

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 Likely_benign. Variant got -2 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=0.06502983).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000525 (80/152324) while in subpopulation NFE AF= 0.000867 (59/68028). AF 95% confidence interval is 0.00069. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.5165G>A	p.Arg1722Gln	missense_variant, splice_region_variant	49/52	ENST00000520908.7
DOCK2	NR_156756.1	n.5268G>A		splice_region_variant, non_coding_transcript_exon_variant	50/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.5165G>A	p.Arg1722Gln	missense_variant, splice_region_variant	49/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000436 AC: 109 AN: 249992 Hom.: 0 AF XY: 0.000444 AC XY: 60 AN XY: 135162

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000656

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000661 AC: 965 AN: 1460658 Hom.: 0 Cov.: 30 AF XY: 0.000701 AC XY: 509 AN XY: 726614

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000779

Gnomad4 OTH exome AF: 0.000647

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74490

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000763 Hom.: 0

Bravo AF: 0.000608

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000545

EpiControl AF: 0.000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DOCK2 deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1722 of the DOCK2 protein (p.Arg1722Gln). This variant is present in population databases (rs199698060, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DOCK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 573836). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.81	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.45	N;.
REVEL	Benign	0.15
Sift	Benign	0.10	T;.
Sift4G	Benign	0.57	T;.
Polyphen		0.74	P;P
Vest4		0.27
MVP		0.66
MPC		0.60
ClinPred		0.040	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.62
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: rs199698060; hg19: chr5-169506149; COSMIC: COSV56955891;