GeneBe

GRIN2B

protein-coding

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

Gene summary

This gene encodes a member of the N-methyl-D-aspartate (NMDA) receptor family within the ionotropic glutamate receptor superfamily. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an agonist binding site for glutamate. The NMDA receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are heterotetramers of seven genetically encoded, differentially expressed subunits including NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Naturally occurring mutations within this gene are associated with neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. [provided by RefSeq, Aug 2017]

Previous symbols:
  • NMDAR2B

MANE transcript

NM_000834.5

Inheritance

AD

ClinVar variants

P:307U:605B:733

Top phenotype

Intellectual developmental disorder, autosomal dominant 6, with or without seizures; Developmental and epileptic encephalopathy 27

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr12:13,437,942-13,982,002

External References & Databases

Ensembl (ENSG00000273079)NCBI Gene (2904)OMIM (138252)HGNC:4586GenCCUniProt (Q13224)AlphaFoldClinVar (GRIN2B)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~544.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 27DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014505

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

GRIN2B was first reported in a series of children with intellectual disability, behavioral issues and abnormal EEG patterns in 2010 (Endele et al 2010, PMID:20890276). Since that time, 94 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported with intellectual disability and associated co-morbidities in humans. For this reason, this gene has been curated using the more comprehensive disease term “complex neurodevelopmental disorder” (MONDO:0100038). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in GRIN2B have been reported in over 100 probands in 28 publications. More evidence is available in the literature, but the maximum score for “definitive” genetic evidence (12 pts.) has been reached. The mechanism for disease is mixed with both loss of function and gain of function observed (PMID: 27818011). This gene-disease association is supported by experimental evidence including in vitro functional assays, expression/localization studies, and animal models (6 pts.). In summary, GRIN2B is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Epilepsy Gene Curation Expert Panel on 3/19/2019 (SOP Version 6).

intellectual developmental disorder, autosomal dominant 6, with or without seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013509

Submitter: G2P

developmental and epileptic encephalopathy, 27STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014505

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 6, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013509

Submitter: Labcorp Genetics (formerly Invitae)

GRIN2B-related complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700350

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 6, with or without seizures; Developmental and epileptic encephalopathy 27AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 20890276; 22521361; 22495309; 23934111; 24272827Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRIN2B variants in ClinVar

47 Conditions Cataloged
Intellectual disability, autosomal dominant 6Total: 1365
Developmental and epileptic encephalopathy, 27Total: 1274
not providedTotal: 604
Inborn genetic diseasesTotal: 225
not specifiedTotal: 192
GRIN2B-related disorderTotal: 83
Complex neurodevelopmental disorderTotal: 33
Intellectual disabilityTotal: 23

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000834.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
14
clinvar
490
clinvar
11
clinvar
 515
missense
30
clinvar
151
clinvar
577
clinvar
158
clinvar
74
clinvar
 990
nonsense
30
clinvar
15
clinvar
2
clinvar
 47
start loss
0
frameshift
38
clinvar
24
clinvar
7
clinvar
 69
splice donor/acceptor (+/-2bp)
12
clinvar
7
clinvar
5
clinvar
 24
Total110197605648851645

Highest pathogenic variant AF is 0.0000065678855

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000834.5RefSeqNP_000825.212MANE Select
ENST00000609686.4EnsemblENSP00000477455.112MANE Select
NM_001413992.1RefSeqNP_001400921.112Standard
NM_001413993.1RefSeqNP_001400922.12Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

Biological Process

  • MAPK cascade
  • glutamate receptor signaling pathway
  • chemical synaptic transmission
  • multicellular organism development
  • brain development

Molecular Function

  • amyloid-beta binding
  • NMDA glutamate receptor activity
  • Ras guanyl-nucleotide exchange factor activity
  • protein binding
  • zinc ion binding

Cellular Component

  • cytoplasm
  • plasma membrane
  • integral component of plasma membrane
  • cell surface
  • postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000609686
Coding exons
12
Length
439889
Individuals with no LoFs
125744
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125748
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense5.424158630.4810.00005519890
Missense (PolyPhen)117379.370.308414480
Synonymous-2.004023541.140.00002512870
Loss of Function6.48048.90.000.00000260603

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000530.000035rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.478

Intolerance Scores

LoFtool
0.169
RVIS EVS
-2.41
RVIS percentile EVS
1.07

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.782

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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