TBC1D24

Chr 16ADAR

TBC1 domain family member 24

Also known as: DEE16, DFNA65, DFNB86, DOORS, EIEE16, EIM, EPRPDC, FIME

NCBI Gene: 57465 ENSG00000162065 UniProt: Q9ULP9

This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 65MIM #616044

Deafness, autosomal recessive 86MIM #614617

Developmental and epileptic encephalopathy 16MIM #615338

DOORS syndromeMIM #220500

Epilepsy, rolandic, with paroxysmal exercise-induce dystonia and writer's crampMIM #608105

Myoclonic epilepsy, infantile, familialMIM #605021

UniProtFamilial infantile myoclonic epilepsy

UniProtDeafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome

1110

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— TBC1D24

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

67 Pathogenic / Likely Pathogenic· 247 VUS of 1110 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.12LOEUF

pLI 0.000

Z-score 1.14

OE 0.73 (0.49–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.76Z-score

OE missense 0.89 (0.81–0.97)

312 obs / 351.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.73 (0.49–1.12)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.81–0.97)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10

0≤1.21.6

LoF obs/exp: 15 / 20.6Missense obs/exp: 312 / 351.9Syn Z: -0.99

ClinVar Variant Classifications

1110 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43

Likely Pathogenic24

VUS247

Likely Benign145

Benign8

Conflicting23

Pathogenic

Likely Pathogenic

247

VUS

145

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	6	20	0	43
Likely Pathogenic	10	10	4	0	24
VUS	2	218	21	6	247
Likely Benign	0	4	43	98	145
Benign	0	0	5	3	8
Conflicting	—				23
Total	29	238	93	107	490

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TBC1D24 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TBC1D24-related DOORS syndrome

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. DisordersSkeletal

G2P ↗

TBC1D24-related myoclonic epilepsy, infantile, familial

definitive

ARUndeterminedAltered Gene Product Structure

Dev. Disorders

G2P ↗

missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

TBC1 DOMAIN FAMILY, MEMBER 24; TBC1D24

MIM #613577 · *

Deafness, autosomal dominant 65

MIM #616044