DOCK8

dedicator of cytokinesis 8, the group of DOCK family Rho GEFs|Armadillo like helical domain containing

Basic information

Region (hg38): 9:214854-465259

Links

ENSG00000107099 ∙ NCBI:81704 ∙ OMIM:611432 ∙ HGNC:19191 ∙ Uniprot:Q8NF50 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined immunodeficiency due to DOCK8 deficiency (Definitive), mode of inheritance: AR
• combined immunodeficiency due to DOCK8 deficiency (Strong), mode of inheritance: AR
• combined immunodeficiency due to DOCK8 deficiency (Moderate), mode of inheritance: AR
• autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
• combined immunodeficiency due to DOCK8 deficiency (Supportive), mode of inheritance: AR
• combined immunodeficiency due to DOCK8 deficiency (Strong), mode of inheritance: AR
• complex neurodevelopmental disorder (Limited), mode of inheritance: AD
• combined immunodeficiency due to DOCK8 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyper-IgE recurrent infection syndrome 2, autosomal recessive	AR	Allergy/Immunology/Infectious; Oncologic	Antiinfectious prophylaxis and early and aggressive treatment of infections can be beneficial; Individuals may also be at higher risk of oncologic complications, including lymphoma and squamous cell carcinomas, and awareness and surveillance may be beneficial in order to allow early detection and treatment; HSCT has been described	Allergy/Immunology/Infectious; Neurologic; Oncologic	2338345; 14722525; 18060736; 18337720; 19776401; 23891736; 24104410; 24106060

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DOCK8 gene.

• Autosomal recessive hyper-IgE syndrome (38 variants)
• not provided (12 variants)
• Combined immunodeficiency due to DOCK8 deficiency (11 variants)
• Inborn genetic diseases (1 variants)
• Inherited Immunodeficiency Diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DOCK8 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			14	442	20	476
missense	1	1	850	13	13	878
nonsense	18	2				20
start loss			1			1
frameshift	26	10	2			38
inframe indel			7			7
splice donor/acceptor (+/-2bp)	6	14	2			22
splice region			43	91	6	140
non coding		2	43	436	241	722
Total	51	29	919	891	274

Highest pathogenic variant AF is 0.0000197

Variants in DOCK8

This is a list of pathogenic ClinVar variants found in the DOCK8 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-214864-C-T		Hyper-IgE syndrome • not specified	Benign (Nov 12, 2023)
9-214871-C-G		not specified	Uncertain significance (Jun 22, 2021)
9-214872-G-T		Combined immunodeficiency due to DOCK8 deficiency	Uncertain significance (Jan 12, 2018)
9-214877-T-A		Combined immunodeficiency due to DOCK8 deficiency	Uncertain significance (Jan 13, 2018)
9-214908-T-C		Combined immunodeficiency due to DOCK8 deficiency	Benign (Jun 19, 2018)
9-214919-C-T		Combined immunodeficiency due to DOCK8 deficiency	Uncertain significance (Jan 13, 2018)
9-214965-C-T		not specified	Likely benign (Oct 26, 2017)
9-214978-T-C		Autosomal recessive hyper-IgE syndrome • Combined immunodeficiency due to DOCK8 deficiency • not specified	Uncertain significance (Jul 15, 2022)
9-214980-G-A		Combined immunodeficiency due to DOCK8 deficiency	Uncertain significance (Sep 01, 2021)
9-214982-C-T		Autosomal recessive hyper-IgE syndrome	Likely benign (Jul 02, 2021)
9-214984-C-G		Autosomal recessive hyper-IgE syndrome	Benign (Oct 05, 2023)
9-214986-C-T		Autosomal recessive hyper-IgE syndrome	Likely benign (Jun 23, 2021)
9-214988-G-T		not specified • Autosomal recessive hyper-IgE syndrome	Likely benign (Jul 27, 2021)
9-214990-C-G		Combined immunodeficiency due to DOCK8 deficiency	Uncertain significance (Apr 19, 2022)
9-214991-G-A		Autosomal recessive hyper-IgE syndrome • DOCK8-related disorder	Benign/Likely benign (Feb 01, 2024)
9-214993-G-T		Autosomal recessive hyper-IgE syndrome	Uncertain significance (Mar 19, 2022)
9-214994-C-T		Autosomal recessive hyper-IgE syndrome	Likely benign (Dec 11, 2023)
9-214998-G-A		Autosomal recessive hyper-IgE syndrome	Uncertain significance (Mar 16, 2023)
9-215000-G-C		Autosomal recessive hyper-IgE syndrome • Inborn genetic diseases	Uncertain significance (Apr 27, 2024)
9-215002-GCC-G		Autosomal recessive hyper-IgE syndrome	Pathogenic (Oct 19, 2022)
9-215003-C-G		Autosomal recessive hyper-IgE syndrome	Likely benign (May 15, 2019)
9-215005-G-A		Inborn genetic diseases	Uncertain significance (Apr 29, 2024)
9-215009-G-A		Autosomal recessive hyper-IgE syndrome	Likely benign (Jun 15, 2022)
9-215010-T-G		Combined immunodeficiency due to DOCK8 deficiency	Uncertain significance (Jan 12, 2018)
9-215012-C-A		Combined immunodeficiency due to DOCK8 deficiency • Autosomal recessive hyper-IgE syndrome	Conflicting classifications of pathogenicity (Oct 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DOCK8	protein_coding	protein_coding	ENST00000453981	48	250406

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.49e-11	1.00	125667	0	81	125748	0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-2.54	1380	1.14e+3	1.21	0.0000679	13855
Missense in Polyphen		427	397.19	1.075		4955
Synonymous	-5.29	589	447	1.32	0.0000279	3982
Loss of Function	6.08	39	107	0.365	0.00000548	1324

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000544	0.000543
Ashkenazi Jewish	0.000200	0.000198
East Asian	0.000381	0.000381
Finnish	0.000140	0.000139
European (Non-Finnish)	0.000301	0.000299
Middle Eastern	0.000381	0.000381
South Asian	0.000555	0.000555
Other	0.000982	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP (PubMed:28028151, PubMed:22461490). During immune responses, required for interstitial dendritic cell (DC) migration by locally activating CDC42 at the leading edge membrane of DC (By similarity). Required for CD4(+) T-cell migration in response to chemokine stimulation by promoting CDC42 activation at T cell leading edge membrane (PubMed:28028151). Is involved in NK cell cytotoxicity by controlling polarization of microtubule-organizing center (MTOC), and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing (PubMed:25762780). {ECO:0000250|UniProtKB:Q8C147, ECO:0000269|PubMed:22461490, ECO:0000269|PubMed:25762780, ECO:0000269|PubMed:28028151}.
• Disease: DISEASE: Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive (AR-HIES) [MIM:243700]: A rare disorder characterized by immunodeficiency, recurrent infections, eczema, increased serum IgE, eosinophilia and lack of connective tissue and skeletal involvement. {ECO:0000269|PubMed:19776401}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, autosomal dominant 2 (MRD2) [MIM:614113]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:18060736}. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration disrupting DOCK8 has been found in a patient with mental retardation and ectodermal dysplasia. A balanced translocation, t(X;9) (q13.1;p24). A genomic deletion of approximately 230 kb in subtelomeric 9p has been detected in a patient with mental retardation.
• Pathway: Factors involved in megakaryocyte development and platelet production;Integrin;Hemostasis (Consensus)

Recessive Scores

• pRec: 0.106

Intolerance Scores

• loftool: 0.630
• rvis_EVS: -1.94
• rvis_percentile_EVS: 1.9

Haploinsufficiency Scores

• pHI: 0.493
• hipred: N
• hipred_score: 0.426
• ghis: 0.570

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.845

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Dock8
• Phenotype: hematopoietic system phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cellular phenotype

Gene ontology

• Biological process: immunological synapse formation;small GTPase mediated signal transduction;blood coagulation;dendritic cell migration;positive regulation of GTPase activity;memory T cell proliferation;negative regulation of T cell apoptotic process;positive regulation of establishment of T cell polarity;cellular response to chemokine;positive regulation of T cell migration
• Cellular component: cytoplasm;cytosol;membrane;leading edge membrane;lamellipodium membrane
• Molecular function: guanyl-nucleotide exchange factor activity;protein binding