GRIN2B

glutamate ionotropic receptor NMDA type subunit 2B, the group of Glutamate ionotropic receptor NMDA type subunits

Basic information

Region (hg38): 12:13437942-13982002

Previous symbols: [ "NMDAR2B" ]

Links

ENSG00000273079NCBI:2904OMIM:138252HGNC:4586Uniprot:Q13224AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • infantile spasms (Supportive), mode of inheritance: AD
  • autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
  • intellectual disability, autosomal dominant 6 (Strong), mode of inheritance: AD
  • developmental and epileptic encephalopathy, 27 (Strong), mode of inheritance: AD
  • complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
  • complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
  • developmental and epileptic encephalopathy, 27 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Intellectual developmental disorder, autosomal dominant 6, with or without seizures; Developmental and epileptic encephalopathy 27ADGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingNeurologic20890276; 22521361; 22495309; 23934111; 24272827
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRIN2B gene.

  • Intellectual disability, autosomal dominant 6 (34 variants)
  • not provided (32 variants)
  • Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 (8 variants)
  • Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 (8 variants)
  • Complex neurodevelopmental disorder (6 variants)
  • Inborn genetic diseases (4 variants)
  • Intellectual disability (3 variants)
  • Developmental and epileptic encephalopathy, 27 (3 variants)
  • GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder (2 variants)
  • Developmental disorder (2 variants)
  • 7 conditions (1 variants)
  • Autism spectrum disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRIN2B gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
13
clinvar
398
clinvar
23
clinvar
434
missense
25
clinvar
105
clinvar
452
clinvar
53
clinvar
59
clinvar
694
nonsense
27
clinvar
8
clinvar
1
clinvar
36
start loss
0
frameshift
22
clinvar
15
clinvar
5
clinvar
42
inframe indel
3
clinvar
22
clinvar
1
clinvar
26
splice donor/acceptor (+/-2bp)
12
clinvar
4
clinvar
1
clinvar
17
splice region
1
9
21
2
33
non coding
9
clinvar
81
clinvar
43
clinvar
133
Total 86 135 503 533 125

Highest pathogenic variant AF is 0.00000658

Variants in GRIN2B

This is a list of pathogenic ClinVar variants found in the GRIN2B region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
12-13561553-C-G Intellectual Disability, Dominant Conflicting classifications of pathogenicity (Nov 01, 2022)307713
12-13562374-A-C Benign (Feb 24, 2021)1281683
12-13562490-C-T Intellectual Disability, Dominant Uncertain significance (Jun 14, 2016)307726
12-13562551-A-G Intellectual Disability, Dominant Uncertain significance (Jun 14, 2016)307729
12-13562669-CAAGA-C Intellectual Disability, Dominant Uncertain significance (Jun 14, 2016)307733
12-13562754-TACCC-T Intellectual Disability, Dominant Uncertain significance (Jun 14, 2016)307735
12-13562783-T-G Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 Uncertain significance (Nov 03, 2024)3759676
12-13562792-A-G Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 Likely benign (May 10, 2024)3753522
12-13562800-TA-T Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Uncertain significance (Mar 22, 2022)856799
12-13562804-A-G Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 Likely benign (Jan 17, 2025)1120312
12-13562806-A-G Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Uncertain significance (Jan 14, 2022)579758
12-13562809-G-C Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Uncertain significance (Nov 10, 2024)1367523
12-13562817-T-C Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Likely benign (Oct 23, 2024)1479105
12-13562822-A-C Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Likely benign (Aug 16, 2022)544239
12-13562822-A-G Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 Likely benign (May 23, 2024)3756501
12-13562825-C-T not specified • Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Likely benign (Oct 29, 2024)245976
12-13562828-A-G Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 • Inborn genetic diseases Likely benign (Oct 16, 2024)391440
12-13562829-T-C Uncertain significance (Jan 07, 2019)2432292
12-13562832-C-T Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Uncertain significance (Jun 25, 2021)1679591
12-13562836-A-G Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 Uncertain significance (Aug 07, 2023)2928981
12-13562838-C-G Uncertain significance (Dec 22, 2014)205726
12-13562839-C-T Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 Uncertain significance (Feb 18, 2024)3762465
12-13562848-C-G Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Uncertain significance (Aug 19, 2024)954907
12-13562853-G-T Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27 Likely benign (Nov 28, 2022)2041767
12-13562858-T-C Inborn genetic diseases Likely benign (Jul 18, 2019)1740158

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
GRIN2Bprotein_codingprotein_codingENST00000609686 12439889
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
1.002.00e-8125744041257480.0000159
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense5.424158630.4810.00005519890
Missense in Polyphen117379.370.308414480
Synonymous-2.004023541.140.00002512870
Loss of Function6.48048.90.000.00000260603

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.000.00
Finnish0.000.00
European (Non-Finnish)0.00005280.0000352
Middle Eastern0.000.00
South Asian0.000.00
Other0.000.00

dbNSFP

Source: dbNSFP

Function
FUNCTION: Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:8768735, PubMed:26919761, PubMed:26875626, PubMed:28126851). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:8768735, PubMed:26875626). In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage. Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death. Contributes to neural pattern formation in the developing brain. Plays a role in long-term depression (LTD) of hippocampus membrane currents and in synaptic plasticity (By similarity). {ECO:0000250|UniProtKB:Q01097, ECO:0000269|PubMed:26875626, ECO:0000269|PubMed:26919761, ECO:0000269|PubMed:28126851, ECO:0000269|PubMed:8768735}.;
Disease
DISEASE: Mental retardation, autosomal dominant 6, with or without seizures (MRD6) [MIM:613970]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD6 additional features may include seizures, hypotonia, abnormal movements, such as dystonia, and autistic features. {ECO:0000269|PubMed:20890276, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23160955, ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:25356899, ECO:0000269|PubMed:27839871, ECO:0000269|PubMed:28095420}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 27 (EIEE27) [MIM:616139]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:24272827, ECO:0000269|PubMed:27839871, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberrations involving GRIN2B has been found in patients with mental retardation. Translocations t(9;12)(p23;p13.1) and t(10;12)(q21.1;p13.1) with a common breakpoint in 12p13.1.;
Pathway
Long-term potentiation - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Systemic lupus erythematosus - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);Nicotine addiction - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Alzheimers Disease;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;NO-cGMP-PKG mediated Neuroprotection;Splicing factor NOVA regulated synaptic proteins;Phosphodiesterases in neuronal function;Ras Signaling;Developmental Biology;Signal Transduction;nitric oxide signaling pathway;GPCR Dopamine D1like receptor;EPH-Ephrin signaling;EPHB-mediated forward signaling;Neuronal System;Synaptic adhesion-like molecules;ErbB4 signaling events;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Neurexins and neuroligins;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Axon guidance;Ras activation upon Ca2+ influx through NMDA receptor;CREB phosphorylation through the activation of Ras;Unblocking of NMDA receptor, glutamate binding and activation;CREB phosphorylation through the activation of CaMKII;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events;Protein-protein interactions at synapses;Reelin signaling pathway (Consensus)

Recessive Scores

pRec
0.478

Intolerance Scores

loftool
0.169
rvis_EVS
-2.41
rvis_percentile_EVS
1.07

Haploinsufficiency Scores

pHI
0.443
hipred
Y
hipred_score
0.778
ghis

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
gene_indispensability_pred
E
gene_indispensability_score
0.782

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Grin2b
Phenotype
nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype;

Gene ontology

Biological process
MAPK cascade;glutamate receptor signaling pathway;chemical synaptic transmission;multicellular organism development;brain development;learning or memory;calcium-mediated signaling;ionotropic glutamate receptor signaling pathway;response to ethanol;ephrin receptor signaling pathway;regulation of synaptic plasticity;protein heterotetramerization;excitatory postsynaptic potential;long-term synaptic potentiation;calcium ion transmembrane import into cytosol;excitatory chemical synaptic transmission;positive regulation of neuron death;negative regulation of dendritic spine maintenance;positive regulation of cysteine-type endopeptidase activity
Cellular component
cytoplasm;plasma membrane;integral component of plasma membrane;cell surface;postsynaptic density;NMDA selective glutamate receptor complex;cell junction;neuron projection;postsynaptic membrane;synaptic membrane;postsynaptic density membrane
Molecular function
amyloid-beta binding;NMDA glutamate receptor activity;Ras guanyl-nucleotide exchange factor activity;protein binding;zinc ion binding;glycine binding;glutamate binding;glutamate-gated calcium ion channel activity