GRID2glutamate receptor, ionotropic, delta 2
Autism Reports / Total Reports
7 / 11Rare Variants / Common Variants
16 / 2Aliases
GRID2, MGC117022, MGC117023, MGC117024Associated Syndromes
-Chromosome Band
4q22.1-q22.2Associated Disorders
-Relevance to Autism
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
Molecular Function
Human glutamate receptor delta-2 (GRID2) is a relatively new member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain. GRID2 is a predicted 1,007 amino acid protein that shares 97% identity with the mouse homolog which is expressed selectively in cerebellar Purkinje cells. GRID2 is strongly suggested to have a role in neuronal apoptotic death.
External Links
SFARI Genomic Platforms
Reports related to GRID2 (11 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Primary | Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders | Schaaf CP , et al. (2011) | Yes | - |
| 2 | Support | Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy | Klassen T , et al. (2011) | No | - |
| 3 | Support | A discovery resource of rare copy number variations in individuals with autism spectrum disorder | Prasad A , et al. (2013) | Yes | - |
| 4 | Support | Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder | Girirajan S , et al. (2013) | Yes | - |
| 5 | Recent Recommendation | A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy | Utine GE , et al. (2013) | No | - |
| 6 | Recent Recommendation | Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans | Hills LB , et al. (2013) | No | - |
| 7 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
| 8 | Support | Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies | Egl P , et al. (2016) | Yes | - |
| 9 | Positive Association | Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia | Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) | Yes | - |
| 10 | Support | - | Grigorenko AP et al. (2022) | No | - |
| 11 | Support | - | Woodbury-Smith M et al. (2022) | Yes | - |
Rare Variants (16)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | copy_number_loss | Familial | Paternal | - | 28356794 | Egl P , et al. (2016) | |
| - | - | copy_number_loss | Unknown | - | Unknown | 23275889 | Prasad A , et al. (2013) | |
| - | - | copy_number_loss | De novo | - | Simplex | 24078737 | Hills LB , et al. (2013) | |
| G>A | - | intron_variant | Unknown | - | Unknown | 21703448 | Klassen T , et al. (2011) | |
| - | - | copy_number_gain | De novo | - | Multiplex | 23375656 | Girirajan S , et al. (2013) | |
| - | - | copy_number_loss | Familial | Maternal | Simplex | 24078737 | Hills LB , et al. (2013) | |
| - | - | copy_number_loss | Familial | Paternal | Simplex | 23375656 | Girirajan S , et al. (2013) | |
| c.1777C>G | p.Pro593Ala | missense_variant | De novo | - | - | 25363760 | De Rubeis S , et al. (2014) | |
| - | - | copy_number_loss | Familial | Both parents | Multiplex | 35159210 | Grigorenko AP et al. (2022) | |
| c.2921T>A | p.Phe974Tyr | missense_variant | Unknown | - | Unknown | 21703448 | Klassen T , et al. (2011) | |
| c.1803G>A | p.Thr601= | synonymous_variant | Unknown | - | Unknown | 21703448 | Klassen T , et al. (2011) | |
| c.2364C>T | p.Ile788%3D | synonymous_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
| - | - | copy_number_loss | Familial | Both parents | Extended multiplex | 23611888 | Utine GE , et al. (2013) | |
| - | - | copy_number_loss | Familial | Both parents | Extended multiplex | 24078737 | Hills LB , et al. (2013) | |
| c.1190C>T | p.Pro397Leu | missense_variant | Familial | Paternal | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.1933G>A | p.Val645Ile | missense_variant | Familial | Paternal | Simplex | 21624971 | Schaaf CP , et al. (2011) |
Common Variants (2)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.244+85419G>C | - | intron_variant | - | - | - | 28540026 | Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) | |
| c.245-47461T>C;c.245-21708T>C;c.281-21708T>C | - | intron_variant | - | - | - | 28540026 | Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) |
SFARI Gene score
2
Strong Candidate
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe 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
3
2
Decreased from 3 to 2
Description
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
10/1/2019
4
3
Decreased from 4 to 3
New Scoring Scheme
Description
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
Reports Added
[New Scoring Scheme]4/1/2017
4
4
Decreased from 4 to 4
Description
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy.2013] [Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans.2013] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies.2016] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017]1/1/2016
4
4
Decreased from 4 to 4
Description
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy.2013] [Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans.2013] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]7/1/2014
No data
4
Increased from No data to 4
Description
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
4/1/2014
No data
4
Increased from No data to 4
Description
Rare mutations in the GRID2 gene have been identified with ASD (Schaaf et al., 2011). In particular, that study found two non-synonymous SNPs in GRID2 in 3 of 339 individuals with ASD.
Krishnan Probability Score
Score 0.4949441209892
Ranking 3322/25841 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.
ExAC Score
Score 0.99999844655582
Ranking 328/18225 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
Sanders TADA Score
Score 0.95026116415794
Ranking 18422/18665 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).
Larsen Cumulative Evidence Score
Score 6
Ranking 257/461 scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.
Zhang D Score
Score -0.2397953421785
Ranking 16196/20870 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.
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| Cbln1 | cerebellin 1 precursor | Mouse | Protein Binding | 12404 | Q9R171 |