5-170055395-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 542624.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-170055395-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.4295+9C>T		intron_variant		ENST00000520908.7
DOCK2	NR_156756.1	n.4398+9C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.4295+9C>T		intron_variant		2	NM_004946.3	P1

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

GnomAD3 exomes AF: 0.00419 AC: 1050 AN: 250874 Hom.: 5 AF XY: 0.00410 AC XY: 556 AN XY: 135574

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.00402

Gnomad4 OTH exome AF: 0.00446

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

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00932

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00322 Hom.: 0

Bravo AF: 0.00269

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

DOCK2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.4
Dann	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs115134653; hg19: chr5-169482399;