GeneBe

RAB23

protein-coding

RAB23, member RAS oncogene family, the group of RAB, member RAS oncogene GTPases

Gene summary

This gene encodes a small GTPase of the Ras superfamily. Rab proteins are involved in the regulation of diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune response to bacterial infection. The encoded protein may play a role in central nervous system development by antagonizing sonic hedgehog signaling. Disruption of this gene has been implicated in Carpenter syndrome as well as cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MANE transcript

NM_016277.5

Inheritance

AR

ClinVar variants

P:42U:97B:89

Top phenotype

Carpenter syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr6:57,186,992-57,222,307

External References & Databases

Ensembl (ENSG00000112210)NCBI Gene (51715)OMIM (606144)HGNC:14263GenCCUniProt (Q9ULC3)AlphaFoldClinVar (RAB23)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~35.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

RAB23-related Carpenter syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008710

Submitter: PanelApp Australia

Carpenter syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019012

Submitter: Orphanet

RAB23-related Carpenter syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008710

Submitter: Natera

RAB23-related Carpenter syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008710

Submitter: ClinGen

RAB23 was first reported in relation to autosomal recessive Carpenter syndrome as early as 2007 (Jenkins et al., PMID: 17503333). At least nine variants (nonsense, frameshift, splice site, in-frame indel, missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. This curation includes five variants reported in five probands to reach a maximum score of 12 points for genetic evidence (PMID: 17503333, 20358613, 23599695, 25168863, 33368989). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature (PMID: 24458945, 21412941). The mechanism of pathogenicity is proposed to be loss of function (PMID: 21412941). This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMID: 32662771, 18218620). In summary, there is definitive evidence to support the relationship between RAB23 and autosomal recessive Carpenter syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the Craniofacial Malformations Gene Curation Expert Panel on 4/22/21 (SOP Version 8).

RAB23-related Carpenter syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008710

Submitter: G2P

RAB23-related Carpenter syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008710

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Carpenter syndrome 1AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Endocrine; Genitourinary; Musculoskeletal; Neurologic

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

Refs: 19974019; 5935752; 3322002; 17503333; 20358613; 21082653; 21412941Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAB23 variants in ClinVar

8 Conditions Cataloged
Carpenter syndromeTotal: 176
RAB23-related disorderTotal: 101
RAB23-related Carpenter syndromeTotal: 63
Inborn genetic diseasesTotal: 32
not providedTotal: 24
not specifiedTotal: 13
Bladder exstrophy-epispadias-cloacal exstrophy complexTotal: 1
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016277.5. 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
2
clinvar
84
clinvar
1
clinvar
 87
missense
1
clinvar
91
clinvar
4
clinvar
 96
nonsense
5
clinvar
6
clinvar
 11
start loss
1
clinvar
 1
frameshift
10
clinvar
8
clinvar
3
clinvar
 21
splice donor/acceptor (+/-2bp)
1
clinvar
11
clinvar
 12
Total172597881228

Highest pathogenic variant AF is 0.0005701954

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_016277.5RefSeqNP_057361.36MANE Select
ENST00000468148.6EnsemblENSP00000417610.16MANE Select
NM_001278666.2RefSeqNP_001265595.16Standard
NM_001278667.2RefSeqNP_001265596.16Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
rab23Danio rerio

Structure: determination of liver left/right asymmetry

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • HH-Ncore
  • miR-targeted genes in lymphocytes - TarBase
  • Post-translational protein modification
  • Metabolism of proteins
  • RAB geranylgeranylation

Biological Process

  • autophagosome assembly
  • intracellular protein transport
  • cellular defense response
  • Rab protein signal transduction
  • negative regulation of protein import into nucleus

Molecular Function

  • GTPase activity
  • protein binding
  • GTP binding

Cellular Component

  • cytoplasm
  • autophagosome
  • centrosome
  • cytosol
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000317483
Coding exons
6
Length
33472
Individuals with no LoFs
125652
Homozygous LoFs
0
Heterozygous LoFs
81
Defined
125733
p
0.000322
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.3181121220.9190.000005851565
Missense (PolyPhen)3843.1950.87972552
Synonymous0.09724343.80.9810.00000229430
Loss of Function2.02614.20.4228.37e-7163

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.000062rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.0000540.000054rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000640.00062rare
South Asian0.0000330.000033rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. Together with SUFU, prevents nuclear import of GLI1, and thereby inhibits GLI1 transcription factor activity. Regulates GLI1 in differentiating chondrocytes. Likewise, regulates GLI3 proteolytic processing and modulates GLI2 and GLI3 transcription factor activity. Plays a role in autophagic vacuole assembly, and mediates defense against pathogens, such as S.aureus, by promoting their capture by autophagosomes that then merge with lysosomes. {ECO:0000269|PubMed:22365972, ECO:0000269|PubMed:22452336}.;
Disease
DISEASE: Carpenter syndrome 1 (CRPT1) [MIM:201000]: A rare autosomal recessive disorder characterized by acrocephaly with variable synostosis of the sagittal, lambdoid, and coronal sutures; peculiar facies; brachydactyly of the hands with syndactyly; preaxial polydactyly and syndactyly of the feet; congenital heart defects; growth retardation; mental retardation; hypogenitalism; and obesity. In addition, cerebral malformations, oral and dental abnormalities, coxa valga, genu valgum, hydronephrosis, precocious puberty, and hearing loss may be observed. {ECO:0000269|PubMed:17503333, ECO:0000269|PubMed:21412941}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.145

Intolerance Scores

LoFtool
0.458
RVIS EVS
0.13
RVIS percentile EVS
63

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.747

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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