GRIA2
protein-codingglutamate ionotropic receptor AMPA type subunit 2, the group of Glutamate ionotropic receptor AMPA type subunits
Gene summary
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and function as ligand-activated cation channels. These channels are assembled from 4 related subunits, GRIA1-4. The subunit encoded by this gene (GRIA2) is subject to RNA editing (CAG->CGG; Q->R) within the second transmembrane domain, which is thought to render the channel impermeable to Ca(2+). Human and animal studies suggest that pre-mRNA editing is essential for brain function, and defective GRIA2 RNA editing at the Q/R site may be relevant to amyotrophic lateral sclerosis (ALS) etiology. Alternative splicing, resulting in transcript variants encoding different isoforms, (including the flip and flop isoforms that vary in their signal transduction properties), has been noted for this gene. [provided by RefSeq, Jul 2008]
- GLUR2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~183.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0030060
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0030060
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0030060
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0030060
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0030060
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0030060
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0030060
Submitter: ClinGen
The GRIA2 gene is located on chromosome 4 at 4q32.1 and encodes the glutamate ionotropic receptor AMPA type subunit 2 protein which functions as a ligand-activated ion channel involved in predominantly excitatory synaptic transmission in mammalian brain. GRIA2 was first reported in relation to autosomal dominant neurodevelopmental disorder with language impairment and behavioral abnormalities in 2019 (Salpietro et al., PMID: 31300657), and is characterized by intellectual disability and neurodevelopmental abnormalities including autism spectrum disorder, speech impairment, developmental regression, Rett syndrome-like features such as head growth deceleration and stereotyped hand movements, and seizures or developmental epileptic encephalopathy. Other reported features include gait disturbances and inability to walk; dystonia; spasticity; joint laxity; hypotonia; ocular concerns; behavioral concerns including obsessive-compulsive behaviors, head banging, and self-injury; sleep disturbances; and cerebellar atrophy and other brain abnormalities. Onset of features occurs in infancy or childhood, and early development may be normal. Ten variants, including seven missense variants, one in-frame deletion and two frameshift variants that have been reported in 12 probands in three publications are included in this curation (PMID: 31300657; Zhou et al., 2021, PMID: 34899870; Latsko et al., 2022, PMID: 35534222). All of these variants occurred de novo and were absent from gnomAD. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by expression, biochemical function, and mouse models. There is neuronal expression of GRIA2 in brain regions. The glutamate ionotropic receptor AMPA type subunits encoded by GRIA1, GRIA3 and GRIA4 have also been associated with autosomal dominant neurodevelopmental disorders. Both homozygous knock-out mice and gain of function knock-in mice expressing a non-desensitising gria2 variant partially recapitulate some aspects of the clinical features (Uhlen et al., 2015, PMID: 25613900; Jia et al., 1996, PMID: 8938126; Christie et al., 2010, PMID: 20439731). In summary, there is definitive evidence to support the relationship between GRIA2 and autosomal dominant GRIA2-neurodevelopmental disorder with language impairment and behavioral abnormalities. 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 Syndromic Disorders GCEP on the meeting date 11.18.2022 (SOP Version 9.0).
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GRIA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001083619.3. 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 | 26 | 4 | 31 | ||
| missense | 5 | 29 | 160 | 6 | 3 | 203 |
| nonsense | 2 | 5 | 7 | |||
| start loss | 0 | |||||
| frameshift | 5 | 1 | 3 | 9 | ||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 12 | 35 | 169 | 32 | 7 | 255 |
Highest pathogenic variant AF is 0.0000068941554
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001077088.2 | 15 | MANE Select | |
| Ensembl | ENSP00000264426.9 | 15 | MANE Select | |
| RefSeq | NP_000817.5 | 15 | Standard | |
| RefSeq | NP_001077089.2 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gria2a | Danio rerio | Structure: anterior lateral line neuromast Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Long-term potentiation - Homo sapiens (human)
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- Dopaminergic synapse - Homo sapiens (human)
- Glutamatergic synapse - Homo sapiens (human)
- Long-term depression - Homo sapiens (human)
Biological Process
- signal transduction
- chemical synaptic transmission
- ion transmembrane transport
- ionotropic glutamate receptor signaling pathway
- synaptic transmission, glutamatergic
Molecular Function
- amyloid-beta binding
- ionotropic glutamate receptor activity
- AMPA glutamate receptor activity
- protein binding
Cellular Component
- endoplasmic reticulum membrane
- plasma membrane
- integral component of plasma membrane
- external side of plasma membrane
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000296526
- Coding exons
- 15
- Length
- 161894
- Individuals with no LoFs
- 125699
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125706
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.56 | 197 | 477 | 0.413 | 0.0000243 | 5804 |
| Missense (PolyPhen) | 42 | 229.41 | 0.18308 | 2839 | ||
| Synonymous | 0.568 | 172 | 182 | 0.946 | 0.0000105 | 1675 |
| Loss of Function | 5.33 | 5 | 42.5 | 0.118 | 0.00000199 | 535 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.000038 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. Through complex formation with NSG1, GRIP1 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (By similarity). {ECO:0000250|UniProtKB:P19491, ECO:0000269|PubMed:20614889}.;
Recessive Scores
- pRec
- 0.258
Intolerance Scores
- LoFtool
- 0.0604
- RVIS EVS
- -0.78
- RVIS percentile EVS
- 12.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.654
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |