chr5-169684341-C-T

Variant names:

• chr5-169684341-C-T
• rs78243868
• NM_004946.3:c.752C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T251T) has been classified 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
• Publications: 7 publications found

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, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

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.752C>T	p.Thr251Met	missense	Exon 8 of 52	NP_004937.1
	DOCK2	NR_156756.1		n.804C>T		non_coding_transcript_exon	Exon 8 of 53

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.752C>T	p.Thr251Met	missense	Exon 8 of 52	ENSP00000429283.3
	DOCK2	ENST00000524185.5	TSL:1	n.752C>T		non_coding_transcript_exon	Exon 8 of 53	ENSP00000428850.1
	DOCK2	ENST00000961039.1		c.752C>T	p.Thr251Met	missense	Exon 8 of 52	ENSP00000631098.1

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

GnomAD2 exomes AF: 0.00924 AC: 2323 AN: 251292 AF XY: 0.00920

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 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

African (AFR) AF: 0.0243 AC: 813 AN: 33476

American (AMR) AF: 0.00532 AC: 238 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 898 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0160 AC: 1384 AN: 86252

European-Finnish (FIN) AF: 0.00258 AC: 138 AN: 53394

Middle Eastern (MID) AF: 0.0208 AC: 120 AN: 5768

European-Non Finnish (NFE) AF: 0.00762 AC: 8474 AN: 1111952

Other (OTH) AF: 0.0112 AC: 676 AN: 60384

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

African (AFR) AF: 0.0247 AC: 1026 AN: 41532

American (AMR) AF: 0.00738 AC: 113 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4830

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00800 AC: 544 AN: 68034

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.0105 Hom.: 40

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DOCK2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.96
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
Vest4		0.16
MVP		0.32
MPC		0.54
ClinPred		0.0017	T
GERP RS		-8.5
Varity_R		0.013
gMVP		0.22
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

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