TBK1

TANK binding kinase 1, the group of I kappa B kinases

Basic information

Region (hg38): 12:64452090-64502114

Links

ENSG00000183735 ∙ NCBI:29110 ∙ OMIM:604834 ∙ HGNC:11584 ∙ Uniprot:Q9UHD2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (Strong), mode of inheritance: AD
• frontotemporal dementia with motor neuron disease (Supportive), mode of inheritance: AD
• encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 (Limited), mode of inheritance: AD
• frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (Strong), mode of inheritance: AD
• frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Encephalopathy, acute, infection-induceed (herpes-specific), susceptibility to, 8	AD	Allergy/Immunology/Infectious	Individuals may be susceptible to severe herpes simplex virus infections including herpes encephalitis has been described, and awareness may allow early diagnosis and treatment, potentially decreasing morbidity and mortality	Allergy/Immunology/Infectious; Neurologic	22851595; 25803835; 25943890

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TBK1 gene.

• Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (37 variants)
• not provided (2 variants)
• Amyotrophic lateral sclerosis (1 variants)
• Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TBK1 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			1	53	6	60
missense	1	1	164	11	2	179
nonsense	11	4				15
start loss			1			1
frameshift	21	3	1			25
inframe indel		1	4	1		6
splice donor/acceptor (+/-2bp)	3	8		1		12
splice region	1		13	14	2	30
non coding			2	60	37	99
Total	36	17	173	126	45

Highest pathogenic variant AF is 0.00000657

Variants in TBK1

This is a list of pathogenic ClinVar variants found in the TBK1 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-64455737-A-T			Likely benign (Feb 18, 2019)
12-64455872-T-C		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Mar 27, 2023)
12-64455874-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Pathogenic (Oct 14, 2022)
12-64455875-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Dec 14, 2023)
12-64455879-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 • TBK1-related disorder	Benign (Dec 19, 2023)
12-64455884-C-A		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (-)
12-64455910-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Sep 03, 2023)
12-64455911-T-C		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Sep 16, 2021)
12-64455921-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Sep 07, 2022)
12-64455934-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Nov 28, 2021)
12-64455936-T-C		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 • Glaucoma 1, open angle, P • not specified	Benign (Jan 31, 2024)
12-64455937-G-A		TBK1-related disorder	Uncertain significance (Jan 16, 2024)
12-64455938-TCT-CC		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Likely pathogenic (Apr 07, 2024)
12-64455939-C-CT		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Pathogenic (Aug 31, 2022)
12-64455943-C-T		TBK1-related disorder	Uncertain significance (Oct 27, 2023)
12-64455949-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Jun 12, 2022)
12-64455952-CA-TT		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Uncertain significance (Feb 18, 2021)
12-64455954-T-TA		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Pathogenic (Jun 07, 2019)
12-64455957-G-A		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Pathogenic (Feb 09, 2018)
12-64455965-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Likely benign (Nov 17, 2023)
12-64455974-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Likely benign (Sep 04, 2023)
12-64456006-G-C			Likely benign (Jul 03, 2019)
12-64456088-C-T			Benign (Jun 26, 2018)
12-64457788-A-G			Benign (Jul 01, 2023)
12-64460180-T-C		Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	Likely benign (Jul 25, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TBK1	protein_coding	protein_coding	ENST00000331710	20	50229

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0752	0.925	125717	0	25	125742	0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.93	267	372	0.718	0.0000188	4792
Missense in Polyphen		73	150.18	0.48609		1928
Synonymous	-0.0615	123	122	1.01	0.00000602	1296
Loss of Function	4.55	11	43.3	0.254	0.00000243	562

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000914	0.0000912
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000147	0.000141
Middle Eastern	0.000109	0.000109
South Asian	0.0000680	0.0000653
Other	0.000360	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser- 177', thus enhancing LC3 binding affinity and antibacterial autophagy (PubMed:21617041). Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation (PubMed:27103069). Phosphorylates and activates AKT1 (PubMed:21464307). Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PubMed:21270402). Phosphorylates Borna disease virus (BDV) P protein (PubMed:16155125). Plays an essential role in the TLR3- and IFN- dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system (PubMed:22851595). {ECO:0000269|PubMed:10581243, ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:12692549, ECO:0000269|PubMed:12702806, ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:15485837, ECO:0000269|PubMed:15489227, ECO:0000269|PubMed:16155125, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:21931631, ECO:0000269|PubMed:22851595, ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:26611359, ECO:0000269|PubMed:27103069}.
• Disease: DISEASE: Glaucoma 1, open angle, P (GLC1P) [MIM:177700]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure. {ECO:0000269|PubMed:21447600, ECO:0000269|PubMed:22306015}. Note=The disease may be caused by mutations affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder (PubMed:21447600). {ECO:0000269|PubMed:21447600}.; DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4) [MIM:616439]: A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. {ECO:0000269|PubMed:25803835, ECO:0000269|PubMed:25943890}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Encephalopathy, acute, infection-induced, herpes- specific, 8 (IIAE8) [MIM:617900]: A rare, often fatal complication of herpes simplex infection, caused by virus spreading in the central nervous system. Disease manifestations include low-grade fever, severe headache, nausea, vomiting, and lethargy. Neurological features include confusion, acute memory disturbances, disorientation, behavioral changes, hemiparesis and seizures. {ECO:0000269|PubMed:22851595, ECO:0000269|PubMed:26513235}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Influenza A - Homo sapiens (human);Mitophagy - animal - Homo sapiens (human);Cytosolic DNA-sensing pathway - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);IL-17 signaling pathway - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;TNF alpha Signaling Pathway;TLR4 Signaling and Tolerance;Toll-like Receptor Signaling;RIG-I-like Receptor Signaling;Ebola Virus Pathway on Host;Chromosomal and microsatellite instability in colorectal cancer;Ebola Virus Pathway on Host;Toll-like Receptor Signaling Pathway;TICAM1-dependent activation of IRF3/IRF7;Toll Like Receptor 3 (TLR3) Cascade;IRF3 mediated activation of type 1 IFN;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;TRAF6 mediated IRF7 activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;STING mediated induction of host immune responses;Regulation of innate immune responses to cytosolic DNA;STAT6-mediated induction of chemokines;Innate Immune System;Immune System;IRF3-mediated induction of type I IFN;TRAF3-dependent IRF activation pathway;Negative regulators of DDX58/IFIH1 signaling;TNFalpha;Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon;Cytosolic sensors of pathogen-associated DNA ;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade (Consensus)

Recessive Scores

• pRec: 0.350

Intolerance Scores

• loftool: 0.541
• rvis_EVS: -0.29
• rvis_percentile_EVS: 33.2

Haploinsufficiency Scores

• pHI: 0.172
• hipred: Y
• hipred_score: 0.792
• ghis: 0.583

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.968

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Tbk1
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; renal/urinary system phenotype; immune system phenotype

Gene ontology

• Biological process: protein phosphorylation;inflammatory response;I-kappaB kinase/NF-kappaB signaling;response to virus;negative regulation of gene expression;viral process;positive regulation of macroautophagy;peptidyl-serine phosphorylation;peptidyl-threonine phosphorylation;regulation of type I interferon production;negative regulation of type I interferon production;positive regulation of type I interferon production;type I interferon production;positive regulation of interferon-alpha production;positive regulation of interferon-beta production;positive regulation of peptidyl-serine phosphorylation;TRIF-dependent toll-like receptor signaling pathway;positive regulation of I-kappaB kinase/NF-kappaB signaling;dendritic cell proliferation;innate immune response;positive regulation of interferon-beta biosynthetic process;positive regulation of transcription by RNA polymerase II;defense response to Gram-positive bacterium;defense response to virus;cellular response to cytokine stimulus;regulation of neuron death;positive regulation of xenophagy
• Cellular component: nucleoplasm;cytoplasm;cytosol;endosome membrane;aggresome
• Molecular function: nucleic acid binding;protein kinase activity;protein serine/threonine kinase activity;protein binding;ATP binding;protein phosphatase binding;identical protein binding;phosphoprotein binding