chr5-170081898-C-T

Position:

• chr5-170081898-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.5344C>T​(p.Arg1782Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,614,098 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (20 hom., cov: 31)
  • Exomes 𝑓: 0.00087 (8 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.33

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=0.0074478686).
• BP6: Variant 5-170081898-C-T is Benign according to our data. Variant chr5-170081898-C-T is described in ClinVar as [Benign]. Clinvar id is 476016.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-170081898-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00751 (1143/152238) while in subpopulation AFR AF= 0.0264 (1095/41514). AF 95% confidence interval is 0.0251. There are 20 homozygotes in gnomad4. There are 500 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.5344C>T	p.Arg1782Cys	missense_variant	51/52	ENST00000520908.7	NP_004937.1
DOCK2	NR_156756.1	n.5447C>T		non_coding_transcript_exon_variant	52/53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.5344C>T	p.Arg1782Cys	missense_variant	51/52	2	NM_004946.3	ENSP00000429283.3

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1138 AN: 152120 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00197 AC: 494 AN: 251368 Hom.: 7 AF XY: 0.00149 AC XY: 203 AN XY: 135856

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000872 AC: 1275 AN: 1461860 Hom.: 8 Cov.: 34 AF XY: 0.000747 AC XY: 543 AN XY: 727238

Gnomad4 AFR exome AF: 0.0292

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00751 AC: 1143 AN: 152238 Hom.: 20 Cov.: 31 AF XY: 0.00672 AC XY: 500 AN XY: 74448

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00206 Hom.: 5

Bravo AF: 0.00881

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.79	.;T
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		1.0	D;D
Vest4		0.65
MVP		0.71
MPC		1.3
ClinPred		0.025	T
GERP RS		4.8
Varity_R		0.17
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs149343589; hg19: chr5-169508902; COSMIC: COSV56952111;