Human Gene Module / Chromosome 4 / GRIA2

GRIA2glutamate ionotropic receptor AMPA type subunit 2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
37 / 0
EAGLE Score
12
Strong Learn More
Aliases
GRIA2, GLUR2,  GLURB,  GluA2,  GluR-K2,  HBGR2
Associated Syndromes
-
Chromosome Band
4q32.1
Associated Disorders
ASD, EPS
Genetic Category
Rare Single Gene Mutation
Relevance to Autism

A de novo nonsense variant in the GRIA2 gene was observed in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo missense variant in GRIA2 was observed in an ASD proband from a multiplex family from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017. Salpietro et al., 2019 reported heterozygous de novo GRIA2 variants in 28 unrelated patients with intellectual disability and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DDE).

Molecular Function

This gene encodes a receptor for glutamate that functions as a 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. This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GRIA2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Recent Recommendation AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders Salpietro V , et al. (2019) No ASD, epilepsy/seizures
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Support - Alkelai A et al. (2021) No Stereotypy
6 Support - Zhou B et al. (2021) No Stereotypy
7 Support - Li D et al. (2022) Yes -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Latsko MS et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Cai Q et al. (2022) Yes -
12 Support - Spataro N et al. (2023) Yes -
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 31300657 Salpietro V , et al. (2019)
c.1474-3C>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.688G>A p.Val230Ile missense_variant Unknown - - 34968013 Li D et al. (2022)
c.699C>A p.Tyr233Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.88+2T>C - splice_site_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.967C>T p.Arg323Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.1844+1G>A - splice_site_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1589A>T p.Lys530Met missense_variant De novo - - 35534222 Latsko MS et al. (2022)
c.1522G>T p.Glu508Ter stop_gained De novo - Simplex 32948840 Alkelai A et al. (2021)
c.905A>G p.Asp302Gly missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.2308G>A p.Ala770Thr missense_variant De novo - Simplex 36329391 Cai Q et al. (2022)
c.317C>G p.Thr106Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1582C>A p.Pro528Thr missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1819C>G p.Arg607Gly missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1825G>A p.Gly609Arg missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1831G>A p.Asp611Asn missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1915G>T p.Ala639Ser missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1932C>A p.Phe644Leu missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1937C>A p.Thr646Asn missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1939G>C p.Val647Leu missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.2328G>T p.Glu776Asp missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.2363G>T p.Trp788Leu missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.2375G>T p.Gly792Val missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.2420C>T p.Ala807Val missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.2435A>G p.Asn812Ser missense_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.1934T>G p.Leu645Arg missense_variant De novo - Simplex 34899870 Zhou B et al. (2021)
c.967C>T p.Arg323Ter stop_gained De novo - Simplex 31300657 Salpietro V , et al. (2019)
c.1650del p.Ile550MetfsTer10 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.345C>G p.Ser115Arg missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.140G>A p.Gly47Glu missense_variant De novo - Simplex 31300657 Salpietro V , et al. (2019)
c.312C>T p.Cys104%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.857del p.Pro286LeufsTer14 frameshift_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.651C>T p.Asn217= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1785del p.Phe595LeufsTer37 frameshift_variant De novo - - 31300657 Salpietro V , et al. (2019)
c.2328G>T p.Glu776Asp missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.345C>G p.Ser115Arg missense_variant De novo - Multiplex 31981491 Satterstrom FK et al. (2020)
c.1582_1590del p.Pro528_Lys530del inframe_deletion De novo - - 31300657 Salpietro V , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
2
icon
1

Decreased from 2 to 1

1/1/2020
2
icon
2

Decreased from 2 to 2

Description

A de novo nonsense variant in the GRIA2 gene was observed in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo missense variant in GRIA2 was observed in an ASD proband from a multiplex family from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017. Salpietro et al., 2019 reported heterozygous de novo GRIA2 variants in 28 unrelated patients with intellectual disability and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DDE).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo nonsense variant in the GRIA2 gene was observed in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo missense variant in GRIA2 was observed in an ASD proband from a multiplex family from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017. Salpietro et al., 2019 reported heterozygous de novo GRIA2 variants in 28 unrelated patients with intellectual disability and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DDE).

Reports Added
[New Scoring Scheme]
7/1/2019
icon
3

Increased from to 3

Description

A de novo nonsense variant in the GRIA2 gene was observed in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, while a de novo missense variant in GRIA2 was observed in an ASD proband from a multiplex family from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017. Salpietro et al., 2019 reported heterozygous de novo GRIA2 variants in 28 unrelated patients with intellectual disability and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DDE).

Krishnan Probability Score

Score 0.76538955618833

Ranking 19/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99550949045347

Ranking 1488/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.50910996005097

Ranking 468/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.46185796113222

Ranking 813/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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