dbSNP rs58980222: DOCK2:p.Arg1064Arg (chr5-170008706-G-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_004946.3(DOCK2):c.3192G>T(p.Arg1064Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,044 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0048 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 25 hom. )

Consequence

DOCK2
NM_004946.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.581

Publications

3 publications found

Variant links:

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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

DOCK2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004946.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 5-170008706-G-T is Benign according to our data. Variant chr5-170008706-G-T is described in ClinVar as Benign. ClinVar VariationId is 542617.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.581 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00484 (737/152236) while in subpopulation EAS AF = 0.0244 (126/5174). AF 95% confidence interval is 0.0209. There are 8 homozygotes in GnomAd4. There are 365 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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.3192G>T	p.Arg1064Arg	synonymous	Exon 32 of 52	NP_004937.1	Q92608-1
	DOCK2	NR_156756.1		n.3295G>T		non_coding_transcript_exon	Exon 33 of 53

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.3192G>T	p.Arg1064Arg	synonymous	Exon 32 of 52	ENSP00000429283.3	Q92608-1
DOCK2	ENST00000524185.5	TSL:1	n.*147G>T		non_coding_transcript_exon	Exon 33 of 53	ENSP00000428850.1	E5RFJ0
DOCK2	ENST00000524185.5	TSL:1	n.*147G>T		3_prime_UTR	Exon 33 of 53	ENSP00000428850.1	E5RFJ0

Frequencies

GnomAD3 genomes

AF:

0.00484

AC:

737

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0243

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00341

AC:

856

AN:

251036

AF XY:

0.00293

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0273

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00138

AC:

2018

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

960

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0125

AC:

420

AN:

33476

American (AMR)

AF:

0.00116

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0269

AC:

1068

AN:

39690

South Asian (SAS)

AF:

0.00384

AC:

331

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111958

Other (OTH)

AF:

0.00199

AC:

120

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

120

241

361

482

602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00484

AC:

737

AN:

152236

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

365

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0133

AC:

551

AN:

41540

American (AMR)

AF:

0.00157

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0244

AC:

126

AN:

5174

South Asian (SAS)

AF:

0.00499

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00551

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

DOCK2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.5

(source)

DANN

Benign

0.66

PhyloP100

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over