Human Gene Module / Chromosome 19 / GRIK5

GRIK5Glutamate receptor, ionotropic, kainate 5

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 10
Rare Variants / Common Variants
11 / 0
Aliases
GRIK5, EAA2,  GRIK2,  GluK5,  KA2
Associated Syndromes
-
Chromosome Band
19q13.2
Associated Disorders
ADHD
Relevance to Autism

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

This gene encodes a protein that belongs to the glutamate-gated ionic channel family and forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GRIK5 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism Sanders SJ , et al. (2012) Yes -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia Takata A , et al. (2016) No -
7 Support Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders Costain G , et al. (2019) Yes ADHD, behavioral problems
8 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
9 Support Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities Koromina M , et al. (2019) Yes -
10 Support - Zhou X et al. (2022) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2134G>A p.Val712Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1992C>T p.Ile664= stop_gained Unknown - Unknown 31844109 Koromina M , et al. (2019)
c.1270-1G>T - splice_site_variant Unknown - Unknown 31844109 Koromina M , et al. (2019)
c.1325G>A p.Arg442His missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1388G>A p.Arg463His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.531G>T p.Leu177= synonymous_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.2684C>G p.Ala895Gly missense_variant Unknown - Unknown 31844109 Koromina M , et al. (2019)
c.2488A>G p.Thr830Ala missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1459G>A p.Glu487Lys missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.1709A>G p.Tyr570Cys missense_variant Unknown - Multiplex 31038196 Callaghan DB , et al. (2019)
c.1840G>A p.Ala614Thr missense_variant Familial - Multi-generational 30732576 Costain G , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

1/1/2020
2
icon
2

Score remained at 2

Description

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities.2019]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.2019]
4/1/2016
3
icon
3

Decreased from 3 to 3

Description

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
icon
3

Increased from to 3

Description

Three de novo missense variants in the GRIK5 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.01) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.57063845334962

Ranking 890/25841 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 0.91777968792704

Ranking 3058/18225 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
Iossifov Probability Score

Score 0.937

Ranking 96/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.68271155032593

Ranking 1055/18665 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 0.300306821285

Ranking 2737/20870 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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