# NM_005993.5(TBCD):c.2009del

https://sugi.bio/variant/tbcd-c-2009del

## Summary

**TBCD c.2009del** is classified **Pathogenic** in TBCD (ClinVar, Single submitter, 2 submitters; last evaluated 2017-10-06). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1555649346 · 2 submitters · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TBCD gene that is reported as disease-causing, but on limited review, submitted by 2 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TBCD](https://sugi.bio/atlas/gene/TBCD/) |
| Coding change (HGVS c.) | c.2009del |
| MANE Select transcript | [NM_005993](https://www.ncbi.nlm.nih.gov/nuccore/NM_005993) |
| dbSNP | [rs1555649346](https://www.ncbi.nlm.nih.gov/snp/rs1555649346/) |
| Variant type | Deletion |
| Location | chr17:82911757-82911757 (GRCh38) |
| ClinVar | [VCV452576](https://www.ncbi.nlm.nih.gov/clinvar/variation/452576/) |

**All HGVS expressions:** `NC_000017.10:g.80869636del`, `NC_000017.11:g.82911760del`, `NG_011721.2:g.164697del`, `NM_005993.5:c.2009del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 9.02, GERP 2.45, phastCons 1 — highly conserved position (PP3-type support)
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TBCD** population constraint: LOEUF 0.763, pLI 2.6388e-20, missense-Z 0.89228. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.45, 77% of residues very-high.

**6 experimental structure(s)** (PDB): [9M1I](https://www.rcsb.org/structure/9M1I), [9M1J](https://www.rcsb.org/structure/9M1J), [9M1K](https://www.rcsb.org/structure/9M1K), [9M1L](https://www.rcsb.org/structure/9M1L), [9M1M](https://www.rcsb.org/structure/9M1M), [9M1N](https://www.rcsb.org/structure/9M1N).

## What this gene does {#gene-function}

*Describes the biological roles of TBCD (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TBCD's established molecular role includes GTPase activator activity.


### Pathways affected {#pathways}

TBCD participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-chaperonin tubulin folding pathway](https://reactome.org/content/detail/R-HSA-389977) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GTPase activator activity, beta-tubulin binding.

**Biological process:** mitotic cell cycle, protein folding, tubulin complex assembly, post-chaperonin tubulin folding pathway, negative regulation of microtubule polymerization, cell morphogenesis involved in neuron differentiation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-10-06.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2017-10-06 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not provided, Hepatocellular carcinoma, none provided.

## Similar variants {#similar}

Related TBCD variant pages (same residue, condition, or type): [TBCD c.1150_1171del](/variant/tbcd-c-1150-1171del), [TBCD c.1272_1318+43del](/variant/tbcd-c-1272-1318-plus-43del), [TBCD p.Glu995fs](/variant/tbcd-p-glu995fs), [TBCD p.Trp705fs](/variant/tbcd-p-trp705fs), [TBCD c.333+20del](/variant/tbcd-c-333-plus-20del), [TBCD c.1302_1318+73del](/variant/tbcd-c-1302-1318-plus-73del), [TBCD c.435+1del](/variant/tbcd-c-435-plus-1del), [TBCD p.Ala510fs](/variant/tbcd-p-ala510fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 452576). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*