Human Gene Module / Chromosome 4 / GRID2

GRID2glutamate receptor, ionotropic, delta 2

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 9
Rare Variants / Common Variants
14 / 2
Aliases
GRID2, MGC117022,  MGC117023,  MGC117024
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
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.

Reports related to GRID2 (9 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 ... Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
Rare Variants   (14)
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)
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 Paternal Simplex 23375656 Girirajan S , et al. (2013)
- p.Gly30_Glu81del copy_number_loss De novo - Simplex 24078737 Hills LB , et al. (2013)
c.1777C>G p.Pro593Ala missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1803G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2921T>A p.Phe974Tyr missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
- p.Gly30_Glu81del copy_number_loss Familial Maternal Simplex 24078737 Hills LB , et al. (2013)
c.1190C>T p.Pro397Leu missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
- - copy_number_loss;copy_number_loss Familial Both parents Multi-generational 23611888 Utine GE , et al. (2013)
c.1933G>A;c.2218G>A p.Val645Ile;p.Val740Ile missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
- p.[Asp177GlyfsTer5];[Asp177GlyfsTer5] copy_number_loss;copy_number_loss Familial Both parents Multi-generational 24078737 Hills LB , et al. (2013)
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
3

Suggestive Evidence

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 4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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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