ATXN2
protein-codingataxin 2
Gene summary
This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
- SCA2
- TNRC13
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~156.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008458
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008458
Submitter: ClinGen
*ATXN2* was first reported in relation to autosomal dominant spinocerebellar ataxia type 2 (SCA2) in 1971 (PMID:5571047). SCA2, due to polyglutamine expansions in *ATXN2*, is characterized by the onset of gait ataxia often along with muscle cramps. Symptoms frequently are reflective of cerebellar neurodegeneration including appendicular ataxia, stance instability and dysarthria (Scoles and Pulst, PMID: 29427103). However, patients often present with symptoms reflective of neurodegneration to other brain areas including the oculomotor brainstem, such as slow or absent saccades, and can present with frontal-executive dysfunction. Polyglutamine expansions in *ATXN2* are also a risk factor for the development of autosomal dominant ALS and late onset autosomal dominant Parkinsons disease. ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, while Parkinsons disease is a neurodegenerative disorder characterized by shaking, stiffness, and difficulty with balance and coordination, brought about by the loss of dopaminergic neruons in the substantia nigra. The size of the expansion and whether the expansion is interrupted may impact disease presentation and onset. Full expansion of the CAG repeat (>33) is a known cause of SCA2, while an intermediate expansion (between 27 and 33) has been associated with risk for ALS, though full CAG repeat expansions in *ATXN2* can also occur in rare cases of ALS. Furthermore, co-existence of SCA2 and ALS with full CAG repeat expansions in ATXN2 has been observed within a family. Given the overlap in genetic variation and the co-occurrence of ALS in individuals and in families, the ALS GCEP determined that ALS, due to CAG repeats >33, would be considered as part of the SCA2 disease spectrum. These ALS cases have been lumped into the curation for SCA2, contributing 3 points to genetic evidence. A total of 12.5 points of genetic evidence were scored through 25 probands from 12 publications (PMIDs: 21307863, 18499737, 20235484, 22700602, 33284045, 17715286, 21537950, 21562247, 21610160, 21670397, 23959108, 24718895) and a summed LOD score of 6.81, although many more probands exist in the literature. Experimentally, this gene-disease relationship is supported by biochemical function including evidence that polyglutamine expansions cause protein misfolding and purkinje cell death in patients with SCA2 (PMID: 29427103). Additionally, experimental evidence is supported by two mouse models with mice expressing separate length repeat expansions. Both mouse models recapitulated core features of SCA2 including severe motor deficits and neuron degeneration and death (PMID: 31376479, PMID: 10973246). Finally, this gene-disease relationship is supported by protein interaction with FUS, and functional alteration showing increased binding to TDP-43 with larger repeat expansion size more robustly associating with TDP-43 (PMIDs: 20740007, 23172909). In summary, *ATXN2* is definitively related to autosomal dominant spinocerebellar ataxia 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. A classification of definitive was approved on 02/16/2024 by the ALS GCEP (SOP version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0008458
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008458
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: 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
Comments: In some individuals, the phenotype may include L-dopa responsive parkinsonism; Homozygosity/compound heterozygosity has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATXN2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001372574.1. 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 | 2 | 18 | 1 | 21 | ||
| missense | 1 | 113 | 14 | 2 | 130 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 8 | 10 | ||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 0 | 2 | 123 | 40 | 3 | 168 |
Highest pathogenic variant AF is 0.00013674526
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001359503.1 | 25 | MANE Select | |
| Ensembl | ENSP00000500925.1 | 25 | MANE Select | |
| RefSeq | NP_001297050.1 | 24 | Standard | |
| RefSeq | NP_001297052.1 | 21 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Parkinsons Disease Pathway
- EGF-EGFR Signaling Pathway
- EGFR1
Biological Process
- negative regulation of receptor internalization
- regulation of translation
- regulation of cytoplasmic mRNA processing body assembly
- RNA metabolic process
- cytoplasmic mRNA processing body assembly
Molecular Function
- RNA binding
- epidermal growth factor receptor binding
- protein binding
- protein C-terminus binding
Cellular Component
- cytoplasm
- Golgi apparatus
- trans-Golgi network
- cytosol
- polysome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000377617
- Coding exons
- 25
- Length
- 147463
- Individuals with no LoFs
- 125698
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 50
- Defined
- 125748
- p
- 0.000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.35 | 466 | 632 | 0.737 | 0.0000344 | 8428 |
| Missense (PolyPhen) | 173 | 288.34 | 0.59999 | 3409 | ||
| Synonymous | 0.675 | 225 | 238 | 0.944 | 0.0000150 | 2678 |
| Loss of Function | 5.48 | 11 | 54.8 | 0.201 | 0.00000267 | 687 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.0018 | 0.0018 | notable |
| East Asian | 0.000058 | 0.000054 | rare |
| Finnish | 0.000051 | 0.000046 | rare |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00034 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane. {ECO:0000269|PubMed:18602463}.;
- Disease
- DISEASE: Spinocerebellar ataxia 2 (SCA2) [MIM:183090]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA2 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. SCA2 is characterized by hyporeflexia, myoclonus and action tremor and dopamine-responsive parkinsonism. In some patients, SCA2 presents as pure familial parkinsonism without cerebellar signs. {ECO:0000269|PubMed:8896555, ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557}. Note=The disease is caused by mutations affecting the gene represented in this entry. SCA2 is caused by expansion of a CAG repeat resulting in about 36 to 52 repeats in some patients. Longer expansions result in earlier the expansion, onset of the disease.; DISEASE: Amyotrophic lateral sclerosis 13 (ALS13) [MIM:183090]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:20740007}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. An increased risk for developing amyotrophic lateral sclerosis seems to be conferred by CAG repeat intermediate expansions greater than 23 but below the threshold for developing spinocerebellar ataxia.;
Recessive Scores
- pRec
- 0.250
Intolerance Scores
- LoFtool
- 0.374
- RVIS EVS
- -1
- RVIS percentile EVS
- 8.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.572
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |