rs780318765

Positions:

• chr5-170019037-C-G
• chr5-170019037-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_004946.3(DOCK2):​c.3310C>G​(p.Arg1104Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1104Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-170019037-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199260.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, DOCK2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.3310C>G	p.Arg1104Gly	missense_variant	33/52	ENST00000520908.7
DOCK2	NR_156756.1	n.3413C>G		non_coding_transcript_exon_variant	34/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.3310C>G	p.Arg1104Gly	missense_variant	33/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461840 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.2	D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		0.99	D;D
Vest4		0.94
MutPred		0.68		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.97
MPC		1.4
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.88
gMVP		0.96

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: rs780318765; hg19: chr5-169446041;