rs144315682

Positions:

• chr5-170082811-G-C
• chr5-170082811-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_004946.3(DOCK2):​c.5446G>C​(p.Ala1816Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1816S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01

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]

DOCK2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DOCK2. . Trascript score misZ 4.9036 (greater than threshold 3.09). GenCC has associacion of gene with DOCK2 deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03195232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.5446G>C	p.Ala1816Pro	missense_variant	52/52	ENST00000520908.7	NP_004937.1
DOCK2	NR_156756.1	n.5549G>C		non_coding_transcript_exon_variant	53/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.5446G>C	p.Ala1816Pro	missense_variant	52/52	2	NM_004946.3	ENSP00000429283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.40
DANN	Benign	0.83
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.60	.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.68	N;.
REVEL	Benign	0.028
Sift	Benign	0.29	T;.
Sift4G	Benign	0.22	T;.
Polyphen		0.010	B;B
Vest4		0.031
MutPred		0.10		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.24
MPC		0.68
ClinPred		0.074	T
GERP RS		-8.2
Varity_R		0.047
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144315682; hg19: chr5-169509815;