5-170082811-G-C

Variant names:

• chr5-170082811-G-C
• rs144315682
• NM_004946.3:c.5446G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 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. 16/22 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
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• DOCK2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03195232).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004946.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	NM_004946.3	MANE Select	c.5446G>C	p.Ala1816Pro	missense	Exon 52 of 52	NP_004937.1
	DOCK2	NR_156756.1		n.5549G>C		non_coding_transcript_exon	Exon 53 of 53

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.5446G>C	p.Ala1816Pro	missense	Exon 52 of 52	ENSP00000429283.3
	DOCK2	ENST00000524185.5	TSL:1	n.*2401G>C		non_coding_transcript_exon	Exon 53 of 53	ENSP00000428850.1
	DOCK2	ENST00000524185.5	TSL:1	n.*2401G>C		3_prime_UTR	Exon 53 of 53	ENSP00000428850.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.0
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
Vest4		0.031
MutPred		0.10		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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs144315682; hg19: chr5-169509815;