GRIN2B

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

Basic information

Region (hg38): 12:13437941-13982002

Previous symbols: [ "NMDAR2B" ]

Links

ENSG00000273079 ∙ NCBI:2904 ∙ OMIM:138252 ∙ HGNC:4586 ∙ Uniprot:Q13224 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autism susceptibility 1 (Definitive), mode of inheritance: AD
• intellectual disability, autosomal dominant 6 (Definitive), mode of inheritance: AD
• West syndrome (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

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, autosomal dominant 6, with or without seizures; Developmental and epileptic encephalopathy 27	AD	General	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	Neurologic	20890276; 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;Developmental and epileptic encephalopathy, 27 (570 variants)
• not provided (435 variants)
• Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6 (267 variants)
• Inborn genetic diseases (161 variants)
• Intellectual disability, autosomal dominant 6 (138 variants)
• not specified (112 variants)
• Developmental and epileptic encephalopathy, 27 (50 variants)
• Complex neurodevelopmental disorder (25 variants)
• Intellectual disability (13 variants)
• GRIN2B-related condition (9 variants)
• Intellectual Disability, Dominant (6 variants)
• See cases (5 variants)
• Developmental disorder (3 variants)
• GRIN2B-Related Disorder (3 variants)
• GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder (2 variants)
• Neurodevelopmental disorder (2 variants)
• Seizure (2 variants)
• Autism spectrum disorder (2 variants)
• Cerebral palsy (1 variants)
• Global developmental delay (1 variants)
• 7 conditions (1 variants)
• intellectual deficiency (1 variants)
• Astigmatism;Delayed speech and language development;Long fingers;Joint hypermobility;Motor delay (1 variants)
• 11 conditions (1 variants)
• Dyssynergia;intellectual deficiency (1 variants)
• Paroxysmal dystonia (1 variants)
• Autistic behavior;Seizure;Atypical behavior;Intellectual disability (1 variants)
• Epileptic encephalopathy (1 variants)
• Seizure;Intellectual disability (1 variants)
• intellectual deficiency;Epilepsy;Dyssynergia (1 variants)
• Landau-Kleffner syndrome (1 variants)
• Intellectual disability, autosomal dominant 6;West syndrome;GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder;Lennox-Gastaut syndrome (1 variants)
• Autosomal dominant non-syndromic intellectual disability (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			16	334	22	372
missense	25	97	350	50	48	570
nonsense	23	7	2			32
start loss						0
frameshift	17	12	5			34
inframe indel		2	16			18
splice donor/acceptor (+/-2bp)	10	3	1			14
splice region	1		8	21	1	31
non coding			9	64	42	115
Total	75	121	399	448	112

Highest pathogenic variant AF is 0.0000131

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)
12-13562374-A-C			Benign (Feb 24, 2021)
12-13562490-C-T		Intellectual Disability, Dominant	Uncertain significance (Jun 14, 2016)
12-13562551-A-G		Intellectual Disability, Dominant	Uncertain significance (Jun 14, 2016)
12-13562669-CAAGA-C		Intellectual Disability, Dominant	Uncertain significance (Jun 14, 2016)
12-13562754-TACCC-T		Intellectual Disability, Dominant	Uncertain significance (Jun 14, 2016)
12-13562800-TA-T		Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6	Uncertain significance (Mar 22, 2022)
12-13562804-A-G		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Likely benign (Sep 07, 2023)
12-13562806-A-G		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Uncertain significance (Jan 14, 2022)
12-13562809-G-C		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Uncertain significance (Jul 05, 2022)
12-13562817-T-C		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Likely benign (Jan 22, 2024)
12-13562822-A-C		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Likely benign (Aug 16, 2022)
12-13562825-C-T		not specified • Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Likely benign (May 13, 2022)
12-13562828-A-G		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Likely benign (Jun 16, 2023)
12-13562829-T-C			Uncertain significance (Jan 07, 2019)
12-13562832-C-T		Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6	Uncertain significance (Jun 25, 2021)
12-13562836-A-G		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Uncertain significance (Aug 07, 2023)
12-13562838-C-G			Uncertain significance (Dec 22, 2014)
12-13562848-C-G		Developmental and epileptic encephalopathy, 27;Intellectual disability, autosomal dominant 6	Uncertain significance (May 01, 2023)
12-13562853-G-T		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Likely benign (Nov 28, 2022)
12-13562858-T-C		Inborn genetic diseases	Likely benign (Jul 18, 2019)
12-13562858-TTTG-T			Uncertain significance (Nov 09, 2023)
12-13562863-T-C		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Benign/Likely benign (Dec 21, 2023)
12-13562883-G-A		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Conflicting classifications of pathogenicity (Dec 11, 2023)
12-13562897-A-G		Intellectual disability, autosomal dominant 6;Developmental and epileptic encephalopathy, 27	Conflicting classifications of pathogenicity (Mar 20, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRIN2B	protein_coding	protein_coding	ENST00000609686	12	439889

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.00e-8	125744	0	4	125748	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.42	415	863	0.481	0.0000551	9890
Missense in Polyphen		117	379.37	0.30841		4480
Synonymous	-2.00	402	354	1.14	0.0000251	2870
Loss of Function	6.48	0	48.9	0.00	0.00000260	603

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000528	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

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

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.782

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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