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GeneBe

rs35887608

Positions:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_004946.3(DOCK2):ā€‹c.2241T>Cā€‹(p.Ile747=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,748 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…).

Frequency

Genomes: š‘“ 0.010 ( 27 hom., cov: 32)
Exomes š‘“: 0.0012 ( 28 hom. )

Consequence

DOCK2
NM_004946.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.13
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.61).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-169718765-T-C is Benign according to our data. Variant chr5-169718765-T-C is described in ClinVar as [Benign]. Clinvar id is 476006.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.13 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1572/152338) while in subpopulation AFR AF= 0.0357 (1483/41570). AF 95% confidence interval is 0.0342. There are 27 homozygotes in gnomad4. There are 735 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DOCK2NM_004946.3 linkuse as main transcriptc.2241T>C p.Ile747= synonymous_variant 22/52 ENST00000520908.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DOCK2ENST00000520908.7 linkuse as main transcriptc.2241T>C p.Ile747= synonymous_variant 22/522 NM_004946.3 P1Q92608-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0103
AC:
1566
AN:
152220
Hom.:
27
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0356
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00347
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000235
Gnomad OTH
AF:
0.00812
GnomAD3 exomes
AF:
0.00279
AC:
701
AN:
251042
Hom.:
10
AF XY:
0.00206
AC XY:
280
AN XY:
135668
show subpopulations
Gnomad AFR exome
AF:
0.0351
Gnomad AMR exome
AF:
0.00174
Gnomad ASJ exome
AF:
0.000199
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000359
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000344
Gnomad OTH exome
AF:
0.00294
GnomAD4 exome
AF:
0.00121
AC:
1772
AN:
1461410
Hom.:
28
Cov.:
30
AF XY:
0.00107
AC XY:
776
AN XY:
727008
show subpopulations
Gnomad4 AFR exome
AF:
0.0379
Gnomad4 AMR exome
AF:
0.00215
Gnomad4 ASJ exome
AF:
0.000574
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000278
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000147
Gnomad4 OTH exome
AF:
0.00298
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0103
AC:
1572
AN:
152338
Hom.:
27
Cov.:
32
AF XY:
0.00987
AC XY:
735
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.0357
Gnomad4 AMR
AF:
0.00346
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00803
Alfa
AF:
0.00182
Hom.:
3
Bravo
AF:
0.0118
Asia WGS
AF:
0.00318
AC:
11
AN:
3476
EpiCase
AF:
0.000545
EpiControl
AF:
0.000593

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

DOCK2 deficiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.61
CADD
Benign
6.7
DANN
Benign
0.74
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35887608; hg19: chr5-169145769; API