TUBB2B

protein-coding

tubulin beta 2B class IIb, the group of Tubulins

Gene summary

The protein encoded by this gene is a beta isoform of tubulin, which binds GTP and is a major component of microtubules. This gene is highly similar to TUBB2A and TUBB2C. Defects in this gene are a cause of asymmetric polymicrogyria. [provided by RefSeq, Mar 2010]

MANE transcript

NM_178012.5

Inheritance

AD, AR

ClinVar variants

P:92U:98B:57

Top phenotype

Cortical dysplasia, complex, with other brain malformations 7

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr6:3,223,324-3,231,730

External References & Databases

Ensembl (ENSG00000137285)

Transcript & Mutation Effects

hg38 • Region Span ~8.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex cortical dysplasia with other brain malformations 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012399

Submitter: PanelApp Australia

cerebellar ataxia, intellectual disability, and dysequilibriumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009133

Submitter: Orphanet

complex cortical dysplasia with other brain malformationsDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000904

Submitter: ClinGen

TUBB2B was first reported in relation to autosomal dominant Complex cortical dysplasia with other brain malformations in 2009 (Jaglin et al., PMID: 19465910). At least 10 unique de novo missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 10 probands in at least 5 publications (PMIDs: 23001566, 22333901, 19465910, 26732629, 25059107). Variants in this gene segregated with disease in 2 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is dominant negative (19465910). This gene-disease relationship is supported by animal models, expression studies, and in vitro functional assays. More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, TUBB2B is definitively associated with autosomal dominant Complex cortical dysplasia with other brain malformations. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 4/26/20 (SOP Version 7).

tubulinopathy-associated dysgyriaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018763

Submitter: Orphanet

congenital fibrosis of extraocular musclesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007614

Submitter: Genomics England PanelApp

complex cortical dysplasia with other brain malformations 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012399

Submitter: G2P

congenital fibrosis of extraocular musclesSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007614

Submitter: Orphanet

complex cortical dysplasia with other brain malformations 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012399

Submitter: Labcorp Genetics (formerly Invitae)

complex cortical dysplasia with other brain malformations 7SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012399

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cortical dysplasia, complex, with other brain malformations 7AD

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: 19465910; 22333901; 23361065; 23495813

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUBB2B variants in ClinVar

12 Conditions Cataloged

not providedTotal: 165

Complex cortical dysplasia with other brain malformations 7Total: 76

not specifiedTotal: 30

TUBB2B-related disorderTotal: 20

Inborn genetic diseasesTotal: 13

LissencephalyTotal: 5

Complex cortical dysplasia with other brain malformations 1Total: 2

TubulinopathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_178012.5. 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			5 clinvar	49 clinvar		54
missense	21 clinvar	70 clinvar	87 clinvar	8 clinvar		186
nonsense		1 clinvar	1 clinvar			2
start loss			1 clinvar			1
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	21	71	98	57	0	247

Highest pathogenic variant AF is 0.000014384566

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_178012.5	RefSeq	NP_821080.1	4	MANE Select
ENST00000259818.8	Ensembl	ENSP00000259818.6	4	MANE Select
ENST00001082973.1	Ensembl	ENSP00000752779.1	4	Standard
ENST00001082974.1	Ensembl	ENSP00000752780.1	4	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
neuron migration
microtubule-based process
modulation of chemical synaptic transmission

Molecular Function

GTPase activity
structural constituent of cytoskeleton
protein binding
GTP binding
protein heterodimerization activity

Cellular Component

nucleus
cytoplasm
microtubule
microtubule cytoskeleton
Schaffer collateral - CA1 synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259818
Coding exons: 4
Length: 7470
Individuals with no LoFs: 114523
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 114524
p: 0.00000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.12	30	264	0.114	0.0000173	2948
Missense (PolyPhen)		9	105.61	0.085216		1218
Synonymous	1.53	100	121	0.823	0.00000962	857
Loss of Function	3.40	0	13.4	0.00	5.78e-7	164

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000034	0.000034	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tubulin is the major constituent of microtubules (PubMed:23001566, PubMed:28013290, PubMed:26732629). 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). Plays a critical role in proper axon guidance in both central and peripheral axon tracts (PubMed:23001566). Implicated in neuronal migration (PubMed:19465910). {ECO:0000250, ECO:0000269|PubMed:19465910, ECO:0000269|PubMed:23001566, ECO:0000269|PubMed:26732629, ECO:0000269|PubMed:28013290}.;
Disease: DISEASE: Cortical dysplasia, complex, with other brain malformations 7 (CDCBM7) [MIM:610031]: A malformation of the cortex in which the brain surface is irregular and characterized by an excessive number of small gyri with abnormal lamination. Polymicrogyria is a heterogeneous disorder, considered to be the result of postmigratory abnormal cortical organization. {ECO:0000269|PubMed:19465910, ECO:0000269|PubMed:22333901, ECO:0000269|PubMed:23001566}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Fetal akinesia deformation sequence (FADS) [MIM:208150]: A clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. Clinical features include fetal akinesia, intrauterine growth retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, craniofacial abnormalities, and cryptorchidism. {ECO:0000269|PubMed:26732629}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in TUBB2B may be involved in cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ). {ECO:0000269|PubMed:28013290}.;

Recessive Scores

pRec: 0.270

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.903