NM_004946.3:c.2800-65392T>C

Variant names:

• chr5-169917676-T-C
• rs33368
• NM_004946.3:c.2800-65392T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004946.3(DOCK2):​c.2800-65392T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 151,896 control chromosomes in the GnomAD database, including 9,929 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9929 hom., cov: 32)
• Consequence: DOCK2 NM_004946.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 0 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]

INSYN2B (HGNC:37271): (inhibitory synaptic factor family member 2B)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK2	NM_004946.3	c.2800-65392T>C		intron_variant	Intron 27 of 51	ENST00000520908.7	NP_004937.1
INSYN2B	NM_001129891.3	c.-918-32860A>G		intron_variant	Intron 1 of 3	ENST00000377365.4	NP_001123363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK2	ENST00000520908.7	c.2800-65392T>C		intron_variant	Intron 27 of 51	2	NM_004946.3	ENSP00000429283.3
INSYN2B	ENST00000377365.4	c.-918-32860A>G		intron_variant	Intron 1 of 3	2	NM_001129891.3	ENSP00000366582.3

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53528 AN: 151778 Hom.: 9921 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.335

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.353 AC: 53563 AN: 151896 Hom.: 9929 Cov.: 32 AF XY: 0.353 AC XY: 26216 AN XY: 74236

African (AFR) AF: 0.455 AC: 18836 AN: 41430

American (AMR) AF: 0.360 AC: 5495 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 952 AN: 3466

East Asian (EAS) AF: 0.534 AC: 2750 AN: 5154

South Asian (SAS) AF: 0.242 AC: 1169 AN: 4822

European-Finnish (FIN) AF: 0.337 AC: 3554 AN: 10534

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19799 AN: 67930

Other (OTH) AF: 0.337 AC: 709 AN: 2104

Alfa AF: 0.304 Hom.: 3840

Bravo AF: 0.361

Asia WGS AF: 0.374 AC: 1304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.26
DANN	Benign	0.57
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs33368; hg19: chr5-169344680;