TRA2B
protein-codingtransformer 2 beta homolog, the group of RNA binding motif containing|Protein phosphatase 1 regulatory subunits
Gene summary
This gene encodes a nuclear protein which functions as sequence-specific serine/arginine splicing factor which plays a role in mRNA processing, splicing patterns, and gene expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]
- SFRS10
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0800439
Submitter: ClinGen
*TRA2B* encodes a splicing regulator. *TRA2B* was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2023 (Ramond et al., PMID: 36549593). Affected individuals present with developmental delay and intellectual disability, frequently associated with hypotonia, infantile spasms, microcephaly, brain abnormalities (including brain atrophy, ventricle enlargement, and corpus callosum hypoplasia), behavioral abnormalities (including autism spectrum disorder), feeding difficulties, and short stature. Eleven *de novo* variants (2 nonsense, 3 splice, and 6 start loss) that have been reported in 11 probands in two publications (PMIDs: 36549593, 37958557) are included in this curation. In addition, a splice variant inherited from a similarly affected parent has been reported (PMID: 36549593). All variants clustered in the 5′ region of *TRA2B*, upstream of an alternative start codon in exon 3. The mechanism of pathogenicity is suggested to be dominant negative, whereby pathogenic variants reduce expression of the canonical Tra2β-1 isoform while increasing expression of the shorter Tra2β-3 isoform, which interferes with the normal function of the canonical protein (PMID: 36549593). However, the possibility of a gain-of-function mechanism — caused by increased expression of the Tra2β-3 protein isoform and leading to changes independent of Tra2β-1 — cannot be ruled out (PMID: 36549593). This gene-disease relationship is also supported by experimental evidence showing splicing defects in a *TRA2B* target gene in patient and non-patient cells carrying a pathogenic variant (PMID: 36549593). In summary, there is definitive evidence supporting the relationship between *TRA2B* and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 6, 2026 (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TRA2B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004593.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 1 | ||||
| missense | 1 | 20 | 1 | 22 | ||
| nonsense | 1 | 1 | ||||
| start loss | 3 | 1 | 4 | |||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 4 | 6 | |||
| Total | 7 | 0 | 28 | 2 | 0 | 37 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004584.1 | 9 | MANE Select | |
| Ensembl | ENSP00000416959.2 | 9 | MANE Select | |
| RefSeq | NP_001230808.1 | 7 | Standard | |
| Ensembl | ENSP00000259043.7 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Spliceosome - Homo sapiens (human)
- mRNA Processing
- Metabolism of RNA
- mRNA Splicing - Major Pathway
- mRNA Splicing
Biological Process
- RNA splicing, via transesterification reactions
- regulation of alternative mRNA splicing, via spliceosome
- mRNA splicing, via spliceosome
- cerebral cortex regionalization
- regulation of RNA splicing
Molecular Function
- RNA binding
- mRNA binding
- protein binding
- protein domain specific binding
- pre-mRNA binding
Cellular Component
- nucleus
- nuclear inner membrane
- nucleoplasm
- spliceosomal complex
- ribonucleoprotein complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000453386
- Coding exons
- 9
- Length
- 22231
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125741
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.50 | 60 | 199 | 0.302 | 0.0000134 | 1816 |
| Missense (PolyPhen) | 1 | 30.616 | 0.032663 | 361 | ||
| Synonymous | 0.0382 | 59 | 59.4 | 0.994 | 0.00000291 | 585 |
| Loss of Function | 3.86 | 1 | 19.3 | 0.0519 | 0.00000125 | 213 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000036 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing. Can either activate or suppress exon inclusion. Acts additively with RBMX to promote exon 7 inclusion of the survival motor neuron SMN2. Activates the splicing of MAPT/Tau exon 10. Alters pre-mRNA splicing patterns by antagonizing the effects of splicing regulators, like RBMX. Binds to the AG-rich SE2 domain in the SMN exon 7 RNA. Binds to pre- mRNA. {ECO:0000269|PubMed:12165565, ECO:0000269|PubMed:12761049, ECO:0000269|PubMed:15009664, ECO:0000269|PubMed:9546399}.;
Recessive Scores
- pRec
- 0.171
Intolerance Scores
- LoFtool
- 0.119
- RVIS EVS
- -0.05
- RVIS percentile EVS
- 49.39
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.609
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Medium |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |