rs34133853

Variant summary

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

The NM_004946.3(DOCK2):ā€‹c.3945T>Cā€‹(p.Tyr1315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,614,150 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…).

Frequency

Genomes: š‘“ 0.0091 ( 29 hom., cov: 32)
Exomes š‘“: 0.00097 ( 20 hom. )

Consequence

DOCK2
NM_004946.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.703
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
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 5-170045884-T-C is Benign according to our data. Variant chr5-170045884-T-C is described in ClinVar as [Benign]. Clinvar id is 476013.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-0.703 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00913 (1391/152290) while in subpopulation AFR AF= 0.0322 (1336/41554). AF 95% confidence interval is 0.0307. There are 29 homozygotes in gnomad4. There are 646 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOCK2NM_004946.3 linkuse as main transcriptc.3945T>C p.Tyr1315= synonymous_variant 39/52 ENST00000520908.7 NP_004937.1
DOCK2NR_156756.1 linkuse as main transcriptn.4048T>C non_coding_transcript_exon_variant 40/53

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOCK2ENST00000520908.7 linkuse as main transcriptc.3945T>C p.Tyr1315= synonymous_variant 39/522 NM_004946.3 ENSP00000429283 P1Q92608-1

Frequencies

GnomAD3 genomes
AF:
0.00912
AC:
1388
AN:
152172
Hom.:
29
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0321
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00236
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00669
GnomAD3 exomes
AF:
0.00240
AC:
602
AN:
251178
Hom.:
10
AF XY:
0.00165
AC XY:
224
AN XY:
135750
show subpopulations
Gnomad AFR exome
AF:
0.0340
Gnomad AMR exome
AF:
0.000867
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000969
Gnomad OTH exome
AF:
0.000979
GnomAD4 exome
AF:
0.000968
AC:
1415
AN:
1461860
Hom.:
20
Cov.:
31
AF XY:
0.000785
AC XY:
571
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0359
Gnomad4 AMR exome
AF:
0.00130
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.00195
GnomAD4 genome
AF:
0.00913
AC:
1391
AN:
152290
Hom.:
29
Cov.:
32
AF XY:
0.00868
AC XY:
646
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0322
Gnomad4 AMR
AF:
0.00235
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00662
Alfa
AF:
0.00531
Hom.:
10
Bravo
AF:
0.0103
Asia WGS
AF:
0.00115
AC:
4
AN:
3476
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

DOCK2 deficiency Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
DOCK2-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 08, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.77
DANN
Benign
0.39
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: rs34133853; hg19: chr5-169472888; API