Human Gene Module / Chromosome 12 / GRIN2B

GRIN2Bglutamate receptor, inotropic, N-methyl D-apartate 2B

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
18 / 48
Rare Variants / Common Variants
126 / 32
Aliases
GRIN2B, NMDAR2B,  NR2B,  hNR3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
12p13.1
Associated Disorders
ASD, DD/NDD, EPS, ADHD, ID, EP
Relevance to Autism

Recurrent mutations in the GRIN2B gene have been identified in multiple individuals with ASD as described below. Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia cases (PMID 21383861). O'Roak et al., 2011 identified an ASD proband from a simplex family with a de novo splice-site variant in GRIN2B; three additional de novo loss-of-function variants in GRIN2B were identified in ASD probands from simplex families in two subsequent reports from O'Roak and colleagues in 2012 (PMIDs 22495309 and 23160955). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified GRIN2B as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Platzer et al., 2017 evaluated 48 novel and 43 previously published individuals with de novo GRIN2B variants; 13 of the 48 novel individuals in this report were reported to have ASD as a phenotype (PMID 28377535). Yoo et al. (2012) showed association of GRIN2B markers in a Korean ASD cohort of 151 families (PMID 22326929); other studies have also found genetic association of the GRIN2B gene with schizophrenia (Ohtsuki et al., 2001) and obsessive-compulsive disorder (Arnold et al., 2004).

Molecular Function

NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium.

Reports related to GRIN2B (48 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Ohtsuki T , et al. (2001) No -
2 Highly Cited Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Arnold PD , et al. (2004) No -
3 Recent Recommendation Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Awadalla P , et al. (2010) No -
4 Support Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Endele S , et al. (2010) No -
5 Recent Recommendation Strain dependent effects of prenatal stress on gene expression in the rat hippocampus. Neeley EW , et al. (2011) No -
6 Recent Recommendation A population genetic approach to mapping neurological disorder genes using deep resequencing. Myers RA , et al. (2011) Yes -
7 Primary Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O'Roak BJ , et al. (2011) Yes -
8 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
9 Positive Association Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders. Yoo HJ , et al. (2012) Yes -
10 Support Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Talkowski ME , et al. (2012) Yes -
11 Support Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Tarabeux J , et al. (2011) Yes -
12 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
13 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
14 Recent Recommendation Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene. Freunscht I , et al. (2013) No -
15 Support Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability. Dimassi S , et al. (2013) No ASD, Epilepsy
16 Positive Association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
17 Support Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Kenny EM , et al. (2013) Yes -
18 Support GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Lemke JR , et al. (2013) No Autistic behavior
19 Support Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA recep... Adams DR , et al. (2014) No Hypoglycemia, lactic acidosis
20 Recent Recommendation Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain. Chuang HC , et al. (2014) No -
21 Positive Association A candidate gene association study further corroborates involvement of contactin genes in autism. Poot M (2014) Yes -
22 Support De novo mutations in moderate or severe intellectual disability. Hamdan FF , et al. (2014) No Microcephaly, absent speech
23 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
24 Support Recurrent de novo mutations implicate novel genes underlying simplex autism risk. O'Roak BJ , et al. (2014) Yes -
25 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
26 Positive Association Association of genetic variants of GRIN2B with autism. Pan Y , et al. (2015) Yes -
27 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
28 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
29 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
30 Support Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. Takasaki Y , et al. (2016) Yes -
31 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
32 Recent Recommendation Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. Swanger SA , et al. (2016) No -
33 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) Yes -
34 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No ASD
35 Support Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights t... Nilsson D , et al. (2016) Yes -
36 Support Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology. Ogden KK , et al. (2017) No -
37 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
38 Support A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density. Liu S , et al. (2017) No -
39 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No Psychomotor retardation
40 Recent Recommendation GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. Platzer K , et al. (2017) No DD, ID, ASD
41 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment. Chen XS , et al. (2017) No -
42 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No Hypotonia, macrocephaly
43 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
44 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. Tumien B , et al. (2017) No -
45 Support Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Fedele L , et al. (2018) No -
46 Recent Recommendation Surface Expression, Function, and Pharmacology of Disease-Associated Mutations in the Membrane Domain of the Human GluN2B Subunit. Vyklicky V , et al. (2018) No -
47 Recent Recommendation Disruption of GRIN2B Impairs Differentiation in Human Neurons. Bell S , et al. (2018) No -
48 Support Atypical Rett Syndrome and Intractable Epilepsy With Novel GRIN2B Mutation. Kyriakopoulos P , et al. (2018) No Stereotypies
Rare Variants   (126)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
T>G p.Leu825Val missense_variant De novo - - 20797689 Awadalla P , et al. (2010)
- - translocation De novo - - 20890276 Endele S , et al. (2010)
- - translocation De novo - - 20890276 Endele S , et al. (2010)
c.411+1G>A p.? splice_site_variant De novo - - 20890276 Endele S , et al. (2010)
c.2044C>T p.Arg682Cys missense_variant De novo - - 20890276 Endele S , et al. (2010)
c.2360-2A>G p.? splice_site_variant De novo - - 20890276 Endele S , et al. (2010)
c.803_804delCA p.Thr268SerfsTer15 frameshift_variant De novo - - 20890276 Endele S , et al. (2010)
c.1768G>A p.Ala590Thr missense_variant Familial - - 20890276 Endele S , et al. (2010)
c.3799G>T p.Ala1267Ser missense_variant Familial Paternal - 20890276 Endele S , et al. (2010)
c.3993G>A p.Met1331Ile missense_variant Unknown - - 20890276 Endele S , et al. (2010)
c.2172-2A>G, c.-43-2A>G - splice_site_variant De novo - Simplex 21572417 O'Roak BJ , et al. (2011)
c.834C>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1440G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4107C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.731C>T p.Ala244Val missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
- - inversion De novo - - 22521361 Talkowski ME , et al. (2012)
c.2473T>G p.Leu825Val missense_variant De novo - Simplex 22833210 Tarabeux J , et al. (2011)
c.3076G>A p.Gly1026Ser missense_variant - - - 22833210 Tarabeux J , et al. (2011)
c.4244C>T p.Ser1415Leu missense_variant - - - 22833210 Tarabeux J , et al. (2011)
c.4270C>T p.Leu1424Phe missense_variant Unknown - - 22833210 Tarabeux J , et al. (2011)
c.4355C>T p.Ser1452Phe missense_variant Unknown - - 22833210 Tarabeux J , et al. (2011)
c.1658C>T p.Pro553Leu missense_variant De novo - - 23033978 de Ligt J , et al. (2012)
c.1677G>A p.Trp559Ter stop_gained De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.1367G>A p.Cys456Tyr missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.99_100insC p.Ser34GlnfsTer25 frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.1906G>C p.Ala636Pro missense_variant De novo - - 23718928 Freunscht I , et al. (2013)
- - copy_number_loss De novo - - 23918416 Dimassi S , et al. (2013)
- - copy_number_loss De novo - - 23918416 Dimassi S , et al. (2013)
- - copy_number_loss De novo - - 23918416 Dimassi S , et al. (2013)
c.1382G>T p.Cys461Phe missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.2131C>T p.Gln711Ter stop_gained De novo - - 24126926 Kenny EM , et al. (2013)
c.1853T>G p.Val618Gly missense_variant De novo - - 24272827 Lemke JR , et al. (2013)
c.1844A>T p.Asn615Ile missense_variant De novo - - 24272827 Lemke JR , et al. (2013)
c.1619G>A p.Arg540His missense_variant De novo - - 24272827 Lemke JR , et al. (2013)
c.2011-5_2011-4delTC p.Phe671_Gln672del splice_site_variant Familial Paternal - 24272827 Lemke JR , et al. (2013)
c.1238A>G p.Glu413Gly missense_variant De novo - - 24863970 Adams DR , et al. (2014)
c.2459G>A p.Gly820Glu missense_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
del(TGAT) - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
del(A) - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1555C>T p.Arg519Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2087G>A p.Arg696His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1619G>A p.Arg540His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3242G>A p.Arg1081His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1573T>G p.Phe525Val missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.2459G>C p.Gly820Ala missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2793C>T p.(=) synonymous_variant Unknown - Simplex 25656819 Pan Y , et al. (2015)
c.2877C>T p.(=) synonymous_variant Unknown - Simplex 25656819 Pan Y , et al. (2015)
c.3429A>G p.(=) synonymous_variant Unknown - Simplex 25656819 Pan Y , et al. (2015)
c.3564C>G p.(=) synonymous_variant Unknown - Simplex 25656819 Pan Y , et al. (2015)
c.3683C>T p.Thr1228Met missense_variant Unknown - Simplex 25656819 Pan Y , et al. (2015)
c.4015A>G p.Met1339Val missense_variant Familial Paternal Simplex 25656819 Pan Y , et al. (2015)
c.3818C>A p.Thr1273Lys missense_variant Familial Paternal Simplex 25656819 Pan Y , et al. (2015)
c.1985A>C p.Gln662Pro missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.1672G>A p.Val558Ile missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1570G>A p.Asp524Asn missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.52G>A p.Val18Ile missense_variant Unknown - - 27616045 Takasaki Y , et al. (2016)
c.1768G>A p.Ala590Thr missense_variant Unknown - - 27616045 Takasaki Y , et al. (2016)
c.3118G>A p.Gly1040Ser missense_variant Unknown - - 27616045 Takasaki Y , et al. (2016)
c.3296G>A p.Arg1099His missense_variant Unknown - - 27616045 Takasaki Y , et al. (2016)
c.3875A>G p.Lys1292Arg missense_variant Unknown - - 27616045 Takasaki Y , et al. (2016)
c.1555C>T p.Arg519Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.2087G>A p.Arg696His missense_variant De novo - Possible multi-generational 27839871 Swanger SA , et al. (2016)
c.1306T>C p.Cys436Arg missense_variant De novo - - 27839871 Swanger SA , et al. (2016)
- - inversion De novo - - 27841880 Redin C , et al. (2016)
c.737C>A p.Ser246Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.2252T>C p.Ile751Thr missense_variant De novo - - 27848944 Trujillano D , et al. (2016)
- - translocation De novo - - 27862604 Nilsson D , et al. (2016)
c.1460G>C p.Gly487Ala missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.2384_2391del p.Leu795HisfsTer7 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.92_99delGCCCCCCCinsGCCCCCCCC p.Ser34GlnfsTer25 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1376G>A p.Gly459Glu missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.2116A>G p.Met706Val missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.448A>G p.Ile150Val missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1306T>C p.Cys436Arg missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1495G>A p.Gly499Arg missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1540A>G p.Thr514Ala missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1547A>G p.Asn516Ser missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1619G>A p.Arg540His missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1623C>G p.Ser541Arg missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1664G>T p.Ser555Ile missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1672G>A p.Val558Ile missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1832G>T p.Gly611Val missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1848C>G p.Asn616Lys missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1883C>G p.Ser628Cys missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1907C>T p.Ala636Val missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1916C>T p.Ala639Val missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1963A>T p.Ile655Phe missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.1970A>G p.Glu657Gly missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2002G>T p.Asp668Tyr missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2065G>A p.Gly689Ser missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2065G>A p.Gly689Ser missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2079A>T p.Arg693Ser missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2084T>C p.Ile695Thr missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2087G>A p.Arg696His missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2087G>A p.Arg696His missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2116A>G p.Met706Val missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2201C>T p.Ala734Val missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2252T>C p.Ile751Thr missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2252T>C p.Ile751Thr missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2252T>C p.Ile751Thr missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2430C>A p.Ser810Arg missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2429G>A p.Ser810Asn missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2452A>C p.Met818Leu missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2453T>C p.Met818Thr missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2455G>A p.Ala819Thr missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2459G>C p.Gly820Ala missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2459G>C p.Gly820Ala missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2459G>C p.Gly820Ala missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2459G>C p.Gly820Ala missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2459G>T p.Gly820Val missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2477G>A p.Gly826Glu missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.2926_2928delAAG p.Lys976del inframe_deletion De novo - - 28377535 Platzer K , et al. (2017)
c.3332G>A p.Arg1111His missense_variant De novo - - 28377535 Platzer K , et al. (2017)
c.538C>T p.Gln180Ter stop_gained De novo - - 28377535 Platzer K , et al. (2017)
c.737C>A p.Ser246Ter stop_gained De novo - - 28377535 Platzer K , et al. (2017)
c.1119G>A p.Trp373Ter stop_gained De novo - - 28377535 Platzer K , et al. (2017)
c.1966C>T p.Gln656Ter stop_gained De novo - - 28377535 Platzer K , et al. (2017)
c.2539C>T p.Arg847Ter stop_gained De novo - - 28377535 Platzer K , et al. (2017)
c.2539C>T p.Arg847Ter stop_gained De novo - - 28377535 Platzer K , et al. (2017)
c.3012C>G p.Tyr1004Ter stop_gained De novo - - 28377535 Platzer K , et al. (2017)
c.4307G>C p.Gly1436Ala missense_variant Familial Paternal Multiplex 28440294 Chen XS , et al. (2017)
c.2053A>C p.Thr685Pro missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.2087G>A p.Arg696His missense_variant De novo - - 28714951 Lim ET , et al. (2017)
G>C p.Tyr869Ter stop_gained De novo - - 28714951 Lim ET , et al. (2017)
c.2395G>A p.Gly799Ser missense_variant De novo - - 29286531 Tumien B , et al. (2017)
c.1928T>C p.Leu643Pro missense_variant De novo - - 30151416 Kyriakopoulos P , et al. (2018)
Common Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.15G>T p.(=) synonymous_variant - - - 11317224 Ohtsuki T , et al. (2001)
c.366C>G p.(=) synonymous_variant - - - 11317224 Ohtsuki T , et al. (2001)
c.1665C>T p.(=) synonymous_variant - - - 11317224 Ohtsuki T , et al. (2001)
c.2664C>T p.(=) synonymous_variant - - - 11317224 Ohtsuki T , et al. (2001)
c.4197T>C p.(=) synonymous_variant - - - 11317224 Ohtsuki T , et al. (2001)
C4615T - 3_prime_UTR_variant - - - 11317224 Ohtsuki T , et al. (2001)
A5806A/C - 3_prime_UTR_variant - - - 11317224 Ohtsuki T , et al. (2001)
5988T/C - 3_prime_UTR_variant - - - 11317224 Ohtsuki T , et al. (2001)
T5072G - 3_prime_UTR_variant - - - 15083261 Arnold PD , et al. (2004)
T5988C - 3_prime_UTR_variant - - - 15083261 Arnold PD , et al. (2004)
c.-19+54228G>A A/G intron_variant - - - 25337070 Poot M (2014)
- G/A downstream_gene_variant - - - 25656819 Pan Y , et al. (2015)
c.2011-14090A>G;c.-43-16037A>G A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.2011-17252A>C;c.-43-19199A>C - intron_variant - - - 25656819 Pan Y , et al. (2015)
c.2010+16493A>G;c.-44+16493A>G A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.2010+10285C>A;c.-44+10285C>A A/C intron_variant - - - 25656819 Pan Y , et al. (2015)
c.2010+8705T>C;c.-44+8705T>C A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1125+15349G>A A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1125+8652A>G A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1125+6440G>A A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1125+3263A>G A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1125+2272T>C - intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1011-13916G>A A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1010+23237C>T G/A intron_variant - - - 25656819 Pan Y , et al. (2015)
c.1010+9696T>C A/G intron_variant - - - 25656819 Pan Y , et al. (2015)
c.412-44918A>C C/A intron_variant - - - 25656819 Pan Y , et al. (2015)
c.412-46045T>C G/A intron_variant - - - 25656819 Pan Y , et al. (2015)
c.411+37406T>G C/A intron_variant - - - 25656819 Pan Y , et al. (2015)
c.411+18164C>A A/C intron_variant - - - 25656819 Pan Y , et al. (2015)
c.411+8818T>C G/A intron_variant - - - 25656819 Pan Y , et al. (2015)
c.4197T>C;c.1983T>C p.(=) synonymous_variant - - - 25656819 Pan Y , et al. (2015)
c.1806C>T;c.-248C>T p.(=) synonymous_variant - - - 25656819 Pan Y , et al. (2015)
SFARI Gene score
1

High Confidence

1

Score Delta: Score remained at 1.1

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.

7/1/2017
1
icon
1

Score remained at 1

Description

Multiple studies have identified rare mutations in the GRIN2B gene with individuals with autism. Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia cases (PMID 21383861). O'Roak et al., 2011 identified an ASD proband from a simplex family with a de novo splice-site variant in GRIN2B; three additional de novo loss-of-function variants in GRIN2B were identified in ASD probands from simplex families in two subsequent reports from O'Roak and colleagues in 2012 (PMIDs 22495309 and 23160955). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified GRIN2B as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Platzer et al., 2017 evaluated 48 novel and 43 previously published individuals with de novo GRIN2B variants; 13 of the 48 novel individuals in this report were reported to have ASD as a phenotype (PMID 28377535). Yoo et al. (2012) showed association of GRIN2B markers in a Korean ASD cohort of 151 families (PMID 22326929); other studies have also found genetic association of the GRIN2B gene with schizophrenia (Ohtsuki et al., 2001) and obsessive-compulsive disorder (Arnold et al., 2004).

4/1/2017
1
icon
1

Score remained at 1

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LoF in GRIN2B. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GRIN2B as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Platzer et al., 2017 evaluated 48 novel and 43 previously published individuals with de novo GRIN2B variants; 13 of the 48 novel individuals in this report were reported to have ASD as a phenotype.

Reports Added
[Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density.2017] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights t...2016] [GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.2017] [Recurrent de novo mutations implicate novel genes underlying simplex autism risk.2014] [De novo mutations in moderate or severe intellectual disability.2014] [Strain dependent effects of prenatal stress on gene expression in the rat hippocampus.2011] [Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.2016] [Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene.2013] [De novo mutations in epileptic encephalopathies.2013] [Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability.2013] [A population genetic approach to mapping neurological disorder genes using deep resequencing.2011] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.2011] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain.2014] [GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.2013] [Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders.2012] [Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.2013] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.2017] [Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population.2016] [Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.2004] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.2010] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology.2017] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [Association of genetic variants of GRIN2B with autism.2015] [Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.2001]
1/1/2017
1
icon
1

Score remained at 1

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LoF in GRIN2B. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GRIN2B as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

10/1/2016
1
icon
1

Score remained at 1

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LoF in GRIN2B. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GRIN2B as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

7/1/2016
1
icon
1

Score remained at 1

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LoF in GRIN2B. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GRIN2B as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

1/1/2016
1
icon
1

Score remained at 1

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LoF in GRIN2B. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GRIN2B as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Strain dependent effects of prenatal stress on gene expression in the rat hippocampus.2011] [Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene.2013] [De novo mutations in epileptic encephalopathies.2013] [Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability.2013] [A population genetic approach to mapping neurological disorder genes using deep resequencing.2011] [Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.2011] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain.2014] [GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.2013] [Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.2013] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.2004] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.2010] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.2001] [Association of genetic variants of GRIN2B with autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
1/1/2015
1
icon
1

Score remained at 1

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LGD in GRIN2B. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GRIN2B as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

10/1/2014
2
icon
1

Decreased from 2 to 1

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LGD in GRIN2B. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GRIN2B as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LGD in GRIN2B.

4/1/2014
No data
icon
2

Increased from No data to 2

Description

Studies have identified rare mutations in the GRIN2B gene with autism. In particular, O'Roak et al. (2011) found a single individual with a 3' splice mutation of GRIN2B, Myers et al. (2011) found an excess of rare non-synonymous mutations in GRIN2B in both autism and schizophrenia. As well, Yoo et al. (2012) showed association of GRIN2B markers in a Korean cohort of 151 families. Studies have also found genetic association of the GRIN2B gene with obsessive-compulsive disorder (Arnold et al., 2004) as well as with schizophrenia (Ohtsuki et al., 2001). PMID 22495309 and 23160955 reported 3 de novo LGD in GRIN2B.

Krishnan Probability Score

Score 0.57893761774073

Ranking 599/25841 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 0.99999489576279

Ranking 400/18225 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
Iossifov Probability Score

Score 0.998

Ranking 8/239 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
Sanders TADA Score

Score 0.00020278814528964

Ranking 15/18665 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 72

Ranking 18/461 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 0.40050735967668

Ranking 1458/20870 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.
CNVs associated with GRIN2B(1 CNVs)
12p13.1 10 Deletion 16  /  18
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
GRIN3A glutamate receptor, ionotropic, N-methyl-D-aspartate 3A Human Protein Binding 116443 Q8TCU5
Il16 interleukin 16 Mouse Protein Binding 16170 O54824
Il1r1 interleukin 1 receptor, type I Rat Protein Binding 25663 Q05KR1
MIR223 microRNA 223 Human RNA Binding 407008 N/A
PLAT plasminogen activator, tissue Human Protein Modification 5327 P00750
Trpv1 transient receptor potential cation channel, subfamily V, member 1 Rat Protein Binding 83810 O35433
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