GeneBe

TBC1D8B

protein-coding

TBC1 domain family member 8B, the group of EF-hand domain containing|GRAM domain containing

Gene summary

This gene encodes a protein with a TBC (Tre-2/Bub2/CDC16) domain. Some mammalian proteins with this domain have been shown to function as Rab-GAPs by binding to specific Rab proteins and affecting their GTPase activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

MANE transcript

NM_017752.3

Inheritance

XL, AD

ClinVar variants

P:11U:360B:52

Top phenotype

Nephrotic syndrome, type 20

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chrX:106,802,673-106,876,150

External References & Databases

Ensembl (ENSG00000133138)NCBI Gene (54885)OMIM (301027)HGNC:24715GenCCUniProt (Q0IIM8)AlphaFoldClinVar (TBC1D8B)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~73.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndrome, type 20MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0026726

Submitter: ClinGen

The *TBC1D8B* gene is located on chromosome X at q22.3 and encodes the protein Tre2-Bub2-Cdc16 (TBC)1 domain family member 8B, which is a GTPase-activating protein for specific Rab GTPases, such as RAB11 that regulate vesicular trafficking of nephrin. *TBC1D8B* was first reported in relation to X-linked early-onset steroid-resistant nephrotic syndrome in 2019 (Dorval et al., PMID: 30661770). The preferred disease name suggested for this disorder is ‘Nephrotic syndrome - *TBC1D8B*’. The mechanism of pathogenicity is known to be loss of function. Nephrotic syndrome - *TBC1D8B* is characterized in existing literature by significant protein loss in the urine causing generalized edema with variable age of onset ranging from the first few months of life to 19 years. Nine variants (frameshift, nonsense and missense) have been reported in 8 probands in 3 publications (PMIDs: 30661770, 31732614, 35970429) and are included in this curation. A total of 6.3/12 pts. for genetic evidence was reached, considering case-level data. This gene-disease association is also supported by animal models, expression studies, in vitro functional assays, and rescue assays. TBC1D8B is expressed on mature human glomeruli (PMID 30661770), interacts with nephrin which is reduced in mutant TBC1D8B (PMID 31732614), and TBC1D8B mutation in vitro increased podocyte motility, increased cell adhesion, and impaired vesicular trafficking (PMID 30661770). TBC1D8B knockout in zebrafish caused glomerular proteinuria, podocyte foot process effacement and pericardial edema (PMID 30661770). Lastly, TBC1D8B knockdown in zebrafish could be rescued using wild-type mRNA (PMID 30661770). A total of 5/6 pts. for experimental evidence was reached. In summary, there is moderate evidence supporting the relationship between TBC1D8B and X-linked Nephrotic syndrome.

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

nephrotic syndrome, type 20STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0026726

Submitter: PanelApp Australia

nephrotic syndrome, type 20LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0026726

Submitter: Ambry Genetics

nephrotic syndrome, type 20STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0026726

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Nephrotic syndrome, type 20XL

Manifestation: Renal

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

Comments: Renal transplant has been described

Refs: 30661770Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBC1D8B variants in ClinVar

5 Conditions Cataloged
not specifiedTotal: 148
not providedTotal: 144
TBC1D8B-related disorderTotal: 30
Nephrotic syndrome, type 20Total: 28
Nephrotic syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017752.3. 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.

EffectPLPVUSLBBSum
synonymous
28
clinvar
23
clinvar
6
clinvar
 57
missense
2
clinvar
2
clinvar
268
clinvar
19
clinvar
2
clinvar
 293
nonsense
1
clinvar
2
clinvar
22
clinvar
 25
start loss
0
frameshift
1
clinvar
3
clinvar
4
clinvar
1
clinvar
 9
splice donor/acceptor (+/-2bp)
38
clinvar
1
clinvar
 39
Total47360448423

Highest pathogenic variant AF is 0.000033980425

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_017752.3RefSeqNP_060222.221MANE Select
ENST00000357242.10EnsemblENSP00000349781.521MANE Select
NM_001441214.1RefSeqNP_001428143.120Standard
NM_001441215.1RefSeqNP_001428144.119Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Golgi Associated Vesicle Biogenesis
  • Clathrin derived vesicle budding
  • trans-Golgi Network Vesicle Budding
  • Vesicle-mediated transport
  • Membrane Trafficking

Biological Process

  • intracellular protein transport
  • activation of GTPase activity

Molecular Function

  • GTPase activator activity
  • calcium ion binding
  • Rab GTPase binding

Cellular Component

  • cell

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000357242
Coding exons
21
Length
73466
Individuals with no LoFs
125646
Homozygous LoFs
27
Heterozygous LoFs
70
Defined
125743
p
0.000386
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.05703723750.9920.00002617389
Missense (PolyPhen)125128.990.969072410
Synonymous0.8381181300.9070.000008672028
Loss of Function2.832039.10.5110.00000291755

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000460.00037rare
Latino/Admixed American0.000820.00061rare
Ashkenazi Jewish0.000690.00050rare
East Asian0.00230.0017notable
Finnish00.0absent
European (Non-Finnish)0.000290.00020rare
South Asian0.000570.00033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May act as a GTPase-activating protein for Rab family protein(s).;

Intolerance Scores

LoFtool
0.645
RVIS EVS
-1.15
RVIS percentile EVS
6.32

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.244

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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