TBC1D28

Chr 17

TBC1 domain family member 28

NCBI Gene: 254272 ENSG00000189375 UniProt: Q2M2D7

The protein functions as a GTPase-activating protein that regulates Rab family GTPases involved in intracellular vesicle trafficking. Mutations cause autosomal recessive developmental and epileptic encephalopathy with severe intellectual disability, seizures, and progressive neurodegeneration. This gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

Research

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.81

Clinical Summary— TBC1D28

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Population Constraint (gnomAD)

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

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ClinVar Variants

34 VUS of 37 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.81LOEUF

pLI 0.000

Z-score -0.51

OE 1.18 (0.74–1.81)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.28Z-score

OE missense 1.08 (0.93–1.25)

122 obs / 113.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.18 (0.74–1.81)

0≤0.351.4

Missense OE?1.08 (0.93–1.25)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 11 / 9.3Missense obs/exp: 122 / 113.5Syn Z: -0.52

This gene — mechanism propensity

0.6938th %ile

GOF

0.4776th %ile

LOF

0.2775th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

37 submitted variants in ClinVar

ClinVar

Classification Summary

VUS34

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	34	34
Likely Benign	2	2
Benign	0	0
Total	36	36

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

View in ClinVar →

102 pathogenic / likely-pathogenic (of 111) ClinVar copy-number / structural variants overlap TBC1D28 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →