Genetic Variant DOCK2:c.43+8C>A (chr5-169637377-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_004946.3(DOCK2):c.43+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000802 in 1,247,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

DOCK2
NM_004946.3 splice_region, intron

Scores

Splicing: ADA: 0.00008948

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.03

Publications

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

DOCK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 5-169637377-C-A is Benign according to our data. Variant chr5-169637377-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2988703.Status of the report is criteria_provided_single_submitter, 1 stars.

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.43+8C>A		splice_region intron	N/A	NP_004937.1	Q92608-1
	DOCK2	NR_156756.1		n.95+8C>A		splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.43+8C>A	splice_region intron	N/A	ENSP00000429283.3	Q92608-1
DOCK2	ENST00000524185.5	TSL:1	n.43+8C>A	splice_region intron	N/A	ENSP00000428850.1	E5RFJ0
DOCK2	ENST00000961039.1		c.43+8C>A	splice_region intron	N/A	ENSP00000631098.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.02e-7

AC:

AN:

1247012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

608962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25342

American (AMR)

AF:

0.00

AC:

AN:

16998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19618

East Asian (EAS)

AF:

0.00

AC:

AN:

27540

South Asian (SAS)

AF:

0.00

AC:

AN:

60670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4668

European-Non Finnish (NFE)

AF:

9.92e-7

AC:

AN:

1007706

Other (OTH)

AF:

0.00

AC:

AN:

50964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely 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

-0.75

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

-1.0

PromoterAI

0.025

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000089

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.39

Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over