rs3763048

Variant names:

• chr5-170034543-C-T
• rs3763048
• NM_004946.3:c.3612C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-170034543-C-T
• chr5-170034543-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004946.3(DOCK2):​c.3612C>T​(p.Thr1204Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,754 control chromosomes in the GnomAD database, including 114,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15154 hom., cov: 33)
  • Exomes 𝑓: 0.36 (98925 hom.)
• Consequence: DOCK2 NM_004946.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -5.00
• Publications: 22 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 5-170034543-C-T is Benign according to our data. Variant chr5-170034543-C-T is described in ClinVar as Benign. ClinVar VariationId is 1165009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	NM_004946.3	MANE Select	c.3612C>T	p.Thr1204Thr	synonymous	Exon 35 of 52	NP_004937.1	Q92608-1
	DOCK2	NR_156756.1		n.3715C>T		non_coding_transcript_exon	Exon 36 of 53

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.3612C>T	p.Thr1204Thr	synonymous	Exon 35 of 52	ENSP00000429283.3	Q92608-1
	DOCK2	ENST00000524185.5	TSL:1	n.*567C>T		non_coding_transcript_exon	Exon 36 of 53	ENSP00000428850.1	E5RFJ0
	DOCK2	ENST00000524185.5	TSL:1	n.*567C>T		3_prime_UTR	Exon 36 of 53	ENSP00000428850.1	E5RFJ0

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65149 AN: 151956 Hom.: 15138 Cov.: 33

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.404

GnomAD2 exomes AF: 0.397 AC: 99645 AN: 250920 AF XY: 0.396

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.580

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.361 AC: 527089 AN: 1461680 Hom.: 98925 Cov.: 41 AF XY: 0.364 AC XY: 264313 AN XY: 727130

African (AFR) AF: 0.613 AC: 20521 AN: 33478

American (AMR) AF: 0.375 AC: 16761 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 10341 AN: 26132

East Asian (EAS) AF: 0.561 AC: 22278 AN: 39688

South Asian (SAS) AF: 0.477 AC: 41157 AN: 86254

European-Finnish (FIN) AF: 0.322 AC: 17157 AN: 53364

Middle Eastern (MID) AF: 0.479 AC: 2761 AN: 5768

European-Non Finnish (NFE) AF: 0.335 AC: 373022 AN: 1111900

Other (OTH) AF: 0.382 AC: 23091 AN: 60392

GnomAD4 genome AF: 0.429 AC: 65222 AN: 152074 Hom.: 15154 Cov.: 33 AF XY: 0.430 AC XY: 31984 AN XY: 74324

African (AFR) AF: 0.609 AC: 25278 AN: 41504

American (AMR) AF: 0.367 AC: 5611 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1348 AN: 3468

East Asian (EAS) AF: 0.576 AC: 2973 AN: 5162

South Asian (SAS) AF: 0.485 AC: 2335 AN: 4810

European-Finnish (FIN) AF: 0.329 AC: 3470 AN: 10560

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22833 AN: 67968

Other (OTH) AF: 0.408 AC: 860 AN: 2110

Alfa AF: 0.373 Hom.: 37117

Bravo AF: 0.442

Asia WGS AF: 0.533 AC: 1856 AN: 3478

EpiCase AF: 0.346

EpiControl AF: 0.357

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	DOCK2 deficiency (2)
-	-	1	not specified (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.19
DANN	Benign	0.63
PhyloP100		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3763048; hg19: chr5-169461547; COSMIC: COSV56944261; COSMIC: COSV56944261;