TUBB2A
protein-codingtubulin beta 2A class IIa, the group of Tubulins
Gene summary
Microtubules, key participants in processes such as mitosis and intracellular transport, are composed of heterodimers of alpha- and beta-tubulins. The protein encoded by this gene is a beta-tubulin. Defects in this gene are associated with complex cortical dysplasia with other brain malformations-5. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2015]
- TUBB
- TUBB2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100153
Submitter: ClinGen
The microtubules are dynamic polymeric structures composed of heterodimers of alpha-tubulins and beta-tubulins, which are continuously incorporated and released. Microtubules play essential roles during brain development, including neurogenesis, neuronal migration, and post-migrational organization. In addition, they participate in mitosis, ciliary/flagellar motility, and intracellular transport. TUBB2A encodes for beta-tubulin 2A. It was first reported in relation to complex cortical dysplasia with other brain malformations-5 in 2014 (Cushion et al., PMID:24702957). It is characterized by variable neuroimaging abnormalities, including corpus callosum anomalies, enlarged ventricles, pachygyria, dysmorphic basal ganglia, cerebellar vermis hypoplasia or dysplasia, and decreased white matter. Epilepsy, intellectual disability/global developmental delay, speech impairment, and motor impairment are frequent features. All phenotypes listed above have been grouped as one disease entity: Tubulinopathy (MONDO:0100153). Evidence supporting this gene-disease relationship includes case-level data only. Summary of Case Level Data: 11.5 POINTS. This curation has 14 missense variants in 20 probands in 6 publications (PMID: 24702957, 28840640, 29547997, 32203252, 33776625, 33776625). 4 probands with the variant p.Ala248Val were not scored due to relatively high allele frequency and reports of VUS and likely benign cases in Clinvar. In summary, there is DEFINITIVE evidence to support this gene-disease relationship. No convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 01/05/2023 (SOP Version 9)
Inheritance Pattern: AD
Disease ID:MONDO:0014337
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0014337
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014337
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014337
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TUBB2A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001069.3. 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 | 141 | 4 | 145 | |||
| missense | 10 | 41 | 114 | 10 | 2 | 177 |
| nonsense | 1 | 7 | 8 | |||
| start loss | 0 | |||||
| frameshift | 7 | 7 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 10 | 42 | 130 | 151 | 6 | 339 |
Highest pathogenic variant AF is 0.00026640698
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001060.1 | 4 | MANE Select | |
| Ensembl | ENSP00000369703.2 | 4 | MANE Select | |
| RefSeq | NP_001297244.1 | 1 | Standard | |
| Ensembl | ENSP00000610115.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Phagosome - Homo sapiens (human)
- Gap junction - Homo sapiens (human)
- Pathogenic Escherichia coli infection - Homo sapiens (human)
- Pathogenic Escherichia coli infection
- Parkin-Ubiquitin Proteasomal System pathway
Biological Process
- microtubule cytoskeleton organization
- mitotic cell cycle
- microtubule-based process
Molecular Function
- GTPase activity
- structural constituent of cytoskeleton
- protein binding
- GTP binding
Cellular Component
- nucleus
- cytoplasm
- microtubule
- extracellular exosome
- extracellular vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000333628
- Coding exons
- 4
- Length
- 3858
- Individuals with no LoFs
- 125713
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125715
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 5.26 | 31 | 278 | 0.112 | 0.0000182 | 2958 |
| Missense (PolyPhen) | 10 | 121.2 | 0.082509 | 1309 | ||
| Synonymous | -0.0636 | 125 | 124 | 1.01 | 0.00000974 | 856 |
| Loss of Function | 3.10 | 1 | 13.1 | 0.0764 | 5.58e-7 | 160 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Cortical dysplasia, complex, with other brain malformations 5 (CDCBM5) [MIM:615763]: A disorder of aberrant neuronal migration and disturbed axonal guidance. Clinical features include seizures, global developmental delay, and various brain malformations such as a diffuse simplified gyral pattern with reduced volume of white matter, globular basal ganglia, thin and dysmorphic corpus callosum, mild brainstem hypoplasia with a flat pons, mild cerebellar vermis hypoplasia, and mildly enlarged posterior fossa. {ECO:0000269|PubMed:24702957}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.336
Intolerance Scores
- LoFtool
- 0.426
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 44.54
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.845
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Low | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Low | Low | Low |