5-169684341-C-T

Position:

• chr5-169684341-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_004946.3(DOCK2):​c.752C>T​(p.Thr251Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00911 in 1,614,052 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (91 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.961

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DOCK2. . Trascript score misZ 4.9036 (greater than threshold 3.09). GenCC has associacion of gene with DOCK2 deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.002072692).
• BP6: Variant 5-169684341-C-T is Benign according to our data. Variant chr5-169684341-C-T is described in ClinVar as [Benign]. Clinvar id is 476018.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1959/152278) while in subpopulation AFR AF= 0.0247 (1026/41532). AF 95% confidence interval is 0.0234. There are 23 homozygotes in gnomad4. There are 908 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.752C>T	p.Thr251Met	missense_variant	8/52	ENST00000520908.7	NP_004937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.752C>T	p.Thr251Met	missense_variant	8/52	2	NM_004946.3	ENSP00000429283.3

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1958 AN: 152160 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00800

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00924 AC: 2323 AN: 251292 Hom.: 22 AF XY: 0.00920 AC XY: 1249 AN XY: 135802

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.0325

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0151

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.00731

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00872 AC: 12745 AN: 1461774 Hom.: 91 Cov.: 30 AF XY: 0.00894 AC XY: 6500 AN XY: 727200

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.00532

Gnomad4 ASJ exome AF: 0.0344

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0160

Gnomad4 FIN exome AF: 0.00258

Gnomad4 NFE exome AF: 0.00762

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0129 AC: 1959 AN: 152278 Hom.: 23 Cov.: 33 AF XY: 0.0122 AC XY: 908 AN XY: 74460

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00800

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00995 Hom.: 24

Bravo AF: 0.0133

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00913 AC: 1108

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00931

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DOCK2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.2
DANN	Benign	0.91
DEOGEN2	Benign	0.096	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.69	.;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.96	N;.
REVEL	Benign	0.045
Sift	Benign	0.15	T;.
Sift4G	Benign	0.10	T;.
Polyphen		0.0050	B;B
Vest4		0.16
MVP		0.32
MPC		0.54
ClinPred		0.0017	T
GERP RS		-8.5
Varity_R		0.013
gMVP		0.22

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

Other links and lift over

dbSNP: rs78243868; hg19: chr5-169111345; COSMIC: COSV99074212; COSMIC: COSV99074212;