Human Gene Module / Chromosome 4 / GRID2

GRID2glutamate receptor, ionotropic, delta 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 11
Rare Variants / Common Variants
16 / 2
Aliases
GRID2, MGC117022,  MGC117023,  MGC117024
Associated Syndromes
-
Chromosome Band
4q22.1-q22.2
Associated 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.

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

2

Strong Candidate

See all Category 2 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
3
icon
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
icon
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]
7/1/2014
No data
icon
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
icon
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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Cbln1 cerebellin 1 precursor Mouse Protein Binding 12404 Q9R171
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