5-170055395-C-T

Variant names:

• chr5-170055395-C-T
• rs115134653
• NM_004946.3:c.4295+9C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004946.3(DOCK2):​c.4295+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,506 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (22 hom.)
• Consequence: DOCK2 NM_004946.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.212
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-170055395-C-T is Benign according to our data. Variant chr5-170055395-C-T is described in ClinVar as Benign. ClinVar VariationId is 542624.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0035 (533/152354) while in subpopulation AMR AF = 0.00464 (71/15306). AF 95% confidence interval is 0.00406. There are 1 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

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.4295+9C>T		intron	N/A	NP_004937.1	Q92608-1
	DOCK2	NR_156756.1		n.4398+9C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.4295+9C>T		intron	N/A	ENSP00000429283.3	Q92608-1
	DOCK2	ENST00000524185.5	TSL:1	n.*1250+9C>T		intron	N/A	ENSP00000428850.1	E5RFJ0
	DOCK2	ENST00000961039.1		c.4256+9C>T		intron	N/A	ENSP00000631098.1

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 533 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00419 AC: 1050 AN: 250874 AF XY: 0.00410

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00391 AC: 5710 AN: 1461152 Hom.: 22 Cov.: 30 AF XY: 0.00380 AC XY: 2764 AN XY: 726924

African (AFR) AF: 0.000687 AC: 23 AN: 33460

American (AMR) AF: 0.00237 AC: 106 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86224

European-Finnish (FIN) AF: 0.0154 AC: 823 AN: 53368

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00402 AC: 4467 AN: 1111430

Other (OTH) AF: 0.00446 AC: 269 AN: 60366

GnomAD4 genome AF: 0.00350 AC: 533 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74494

African (AFR) AF: 0.00113 AC: 47 AN: 41582

American (AMR) AF: 0.00464 AC: 71 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00932 AC: 99 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00317 Hom.: 0

Bravo AF: 0.00269

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.56
PhyloP100		-0.21
Mutation Taster		=100/0	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: rs115134653; hg19: chr5-169482399;