TTBK2

protein-coding

tau tubulin kinase 2

Gene summary

This gene encodes a serine-threonine kinase that putatively phosphorylates tau and tubulin proteins. Mutations in this gene cause spinocerebellar ataxia type 11 (SCA11); a neurodegenerative disease characterized by progressive ataxia and atrophy of the cerebellum and brainstem. [provided by RefSeq, Aug 2009]

Previous symbols:

SCA11

MANE transcript

NM_173500.4

Inheritance

ClinVar variants

P:13U:313B:128

Top phenotype

Spinocerebellar ataxia 11

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr15:42,738,730-42,920,809

External References & Databases

Ensembl (ENSG00000128881)

Transcript & Mutation Effects

hg38 • Region Span ~182.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011464

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011464

Submitter: PanelApp Australia

spinocerebellar ataxia type 11SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011464

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 11AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 18037885

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TTBK2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 341

Inborn genetic diseasesTotal: 146

not specifiedTotal: 80

Spinocerebellar ataxia type 11Total: 70

TTBK2-related disorderTotal: 19

Spastic ataxiaTotal: 1

Hereditary ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173500.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			14 clinvar	75 clinvar	5 clinvar	94
missense		1 clinvar	287 clinvar	44 clinvar	4 clinvar	336
nonsense	1 clinvar	3 clinvar	4 clinvar			8
start loss						0
frameshift	5 clinvar	3 clinvar	5 clinvar			13
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	6	7	313	119	9	454

Highest pathogenic variant AF is 0.000004788309

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173500.4	RefSeq	NP_775771.3	14	MANE Select
ENST00000267890.11	Ensembl	ENSP00000267890.6	14	MANE Select
ENST00000562880.5	Ensembl	ENSP00000457385.1	4	Standard
ENST00000564431.5	Ensembl	ENSP00000455574.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Anchoring of the basal body to the plasma membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

microtubule cytoskeleton organization
negative regulation of microtubule depolymerization
smoothened signaling pathway
peptidyl-serine phosphorylation
peptidyl-threonine phosphorylation

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding
kinesin binding

Cellular Component

extracellular space
nucleus
cytoplasm
centriole
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000267890
Coding exons: 14
Length: 182076
Individuals with no LoFs: 124785
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 124800
p: 0.0000601

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.39	558	659	0.847	0.0000351	8132
Missense (PolyPhen)		177	269.56	0.65662		3170
Synonymous	0.0958	232	234	0.992	0.0000118	2495
Loss of Function	5.66	7	50.3	0.139	0.00000292	617

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to the recruitment of IFT proteins, which build the ciliary axoneme. Has some substrate preference for proteins that are already phosphorylated on a Tyr residue at the +2 position relative to the phosphorylation site. Able to phosphorylate tau on serines in vitro. {ECO:0000269|PubMed:21548880, ECO:0000269|PubMed:23141541}.;
Disease: DISEASE: Spinocerebellar ataxia 11 (SCA11) [MIM:604432]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA11 is an autosomal dominant cerebellar ataxia (ADCA). It is a relatively benign, late-onset, slowly progressive neurologic disorder. {ECO:0000269|PubMed:18037885}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0844

Intolerance Scores

LoFtool: 0.435
RVIS EVS: -0.66
RVIS percentile EVS: 16.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.993

Gene Damage Prediction

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