TBCD

tubulin folding cofactor D, the group of Armadillo like helical domain containing

Basic information

Region (hg38): 17:82752042-82945914

Links

ENSG00000141556 ∙ NCBI:6904 ∙ OMIM:604649 ∙ HGNC:11581 ∙ Uniprot:Q9BTW9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (Strong), mode of inheritance: AR
• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT)	AR	General	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	Craniofacial; Neurologic	27666370; 27666374

ClinVar

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

• not provided (39 variants)
• Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (6 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TBCD 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	372	18	391
missense	1	9	192	25	7	234
nonsense	21	4	2			27
start loss						0
frameshift	17	3				20
inframe indel			4			4
splice donor/acceptor (+/-2bp)	3	17	1		2	23
splice region	1	1	9	87	7	105
non coding			44	309	101	454
Total	42	33	244	706	128

Highest pathogenic variant AF is 0.0000328

Variants in TBCD

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

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

Position	Type	Phenotype	Significance	ClinVar
17-82752160-CG-C			Benign (May 21, 2021)
17-82752188-G-T		TBCD-related disorder	Uncertain significance (Mar 01, 2022)
17-82752198-C-T			Uncertain significance (Nov 30, 2021)
17-82752200-C-T			Likely benign (Sep 01, 2023)
17-82752202-G-C			Likely benign (Jan 11, 2024)
17-82752203-A-T		Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	Uncertain significance (May 21, 2020)
17-82752209-G-T			Pathogenic (Dec 14, 2023)
17-82752211-A-G			Likely benign (Nov 11, 2023)
17-82752214-G-A			Likely benign (Dec 28, 2023)
17-82752219-CG-C			Pathogenic (Aug 18, 2023)
17-82752220-G-A			Likely benign (Sep 14, 2023)
17-82752221-G-T		Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	Benign (Jan 31, 2024)
17-82752222-G-A		Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	Conflicting classifications of pathogenicity (Jan 04, 2024)
17-82752223-C-T			Benign (Jan 31, 2024)
17-82752229-C-G			Likely benign (Jan 13, 2024)
17-82752229-CGAG-C			Uncertain significance (Dec 02, 2021)
17-82752235-G-A			Likely benign (Nov 22, 2023)
17-82752241-G-A			Likely benign (Jun 23, 2023)
17-82752244-G-A			Likely benign (Jun 09, 2023)
17-82752247-C-G		Inborn genetic diseases	Uncertain significance (Aug 11, 2022)
17-82752247-C-T			Likely benign (May 12, 2023)
17-82752250-G-A			Likely benign (Dec 01, 2023)
17-82752253-A-T			Likely benign (Jan 01, 2024)
17-82752254-C-T			Likely benign (Jan 25, 2024)
17-82752259-C-T			Likely benign (Dec 06, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TBCD	protein_coding	protein_coding	ENST00000355528	39	190785

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00e-7	1.00	124866	0	67	124933	0.000268

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.82	573	710	0.807	0.0000452	7659
Missense in Polyphen		144	225.85	0.6376		2396
Synonymous	-0.177	303	299	1.01	0.0000216	2344
Loss of Function	5.11	26	73.1	0.356	0.00000391	804

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000887	0.000883
Ashkenazi Jewish	0.0000995	0.0000993
East Asian	0.000167	0.000167
Finnish	0.00	0.00
European (Non-Finnish)	0.000233	0.000221
Middle Eastern	0.000167	0.000167
South Asian	0.000301	0.000294
Other	0.000166	0.000164

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly. Involved in the regulation of microtubule polymerization or depolymerization, it modulates microtubule dynamics by capturing GTP-bound beta-tubulin (TUBB). Its ability to interact with beta tubulin is regulated via its interaction with ARL2. Acts as a GTPase-activating protein (GAP) for ARL2. Induces microtubule disruption in absence of ARL2. Increases degradation of beta tubulin, when overexpressed in polarized cells. Promotes epithelial cell detachment, a process antagonized by ARL2. Induces tight adherens and tight junctions disassembly at the lateral cell membrane (PubMed:10722852, PubMed:10831612, PubMed:11847227, PubMed:20740604, PubMed:27666370, PubMed:28158450). Required for correct assembly and maintenance of the mitotic spindle, and proper progression of mitosis (PubMed:27666370). Involved in neuron morphogenesis (PubMed:27666374). {ECO:0000269|PubMed:10722852, ECO:0000269|PubMed:10831612, ECO:0000269|PubMed:11847227, ECO:0000269|PubMed:20740604, ECO:0000269|PubMed:27666370, ECO:0000269|PubMed:27666374, ECO:0000269|PubMed:28158450}.
• Disease: DISEASE: Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum (PEBAT) [MIM:617193]: An autosomal recessive disease with neurodevelopmental and neurodegenerative features. PEBAT is characterized by early-onset cortical atrophy, hypomyelination, microcephaly, thin corpus callosum, delayed psychomotor development, developmental regression, intellectual disability, seizures, optic atrophy, muscle weakness and atrophy, spastic quadriplegia, and respiratory insufficiency due to hypotonia. {ECO:0000269|PubMed:27666370, ECO:0000269|PubMed:27666374, ECO:0000269|PubMed:27807845, ECO:0000269|PubMed:28158450}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Metabolism of proteins;Protein folding;Post-chaperonin tubulin folding pathway (Consensus)

Recessive Scores

• pRec: 0.110

Intolerance Scores

• loftool: 0.799
• rvis_EVS: -1.45
• rvis_percentile_EVS: 3.89

Haploinsufficiency Scores

• pHI: 0.122
• hipred: Y
• hipred_score: 0.605
• ghis: 0.657

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.842

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tbcd

Zebrafish Information Network

• Gene name: tbcd
• Affected structure: muscle cell
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: microtubule cytoskeleton organization;mitotic cell cycle;protein folding;tubulin complex assembly;post-chaperonin tubulin folding pathway;negative regulation of cell-substrate adhesion;negative regulation of microtubule polymerization;adherens junction assembly;positive regulation of GTPase activity;cell morphogenesis involved in neuron differentiation;bicellular tight junction assembly
• Cellular component: cytoplasm;centrosome;microtubule;adherens junction;bicellular tight junction;lateral plasma membrane
• Molecular function: GTPase activator activity;protein binding;beta-tubulin binding;chaperone binding