GRIN2A

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

Basic information

Region (hg38): 16:9753403-10182928

Previous symbols: [ "NMDAR2A" ]

Links

ENSG00000183454 ∙ ∙ OMIM:138253 ∙ HGNC:4585 ∙ Uniprot:Q12879 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Landau-Kleffner syndrome (Definitive), mode of inheritance: AD
• Landau-Kleffner syndrome (Strong), mode of inheritance: AD
• childhood epilepsy with centrotemporal spikes (Supportive), mode of inheritance: AD
• continuous spikes and waves during sleep (Supportive), mode of inheritance: AD
• Landau-Kleffner syndrome (Supportive), mode of inheritance: AD
• rolandic epilepsy-speech dyspraxia syndrome (Supportive), mode of inheritance: AD
• early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation (Supportive), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
• Landau-Kleffner syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, focal, with speech disorder and with or without impaired intellectual development	AD	Neurologic	Individuals may manifest with seizures, and specific knowledge of the underlying cause can help direct selection of optimal therapies for management based on the genetic etiology	Neurologic	20890276; 23933818; 23933819; 23933820; 24504326; 28212175; 28331464; 30870728

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRIN2A gene.

• Landau-Kleffner syndrome (1491 variants)
• not provided (493 variants)
• Inborn genetic diseases (161 variants)
• not specified (140 variants)
• Childhood epilepsy with centrotemporal spikes (11 variants)
• Intellectual disability (10 variants)
• GRIN2A-related condition (9 variants)
• See cases (6 variants)
• Complex neurodevelopmental disorder (4 variants)
• Neurodevelopmental disorder (4 variants)
• Epileptic encephalopathy (2 variants)
• Seizure (2 variants)
• Pyridoxine-dependent epilepsy (1 variants)
• Focal epilepsy (1 variants)
• Abnormal cerebral morphology (1 variants)
• Global developmental delay (1 variants)
• Epilepsy, familial temporal lobe, 1 (1 variants)
• Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation (1 variants)
• Seizure;Intellectual disability (1 variants)
• Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome (1 variants)
• History of neurodevelopmental disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRIN2A 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			23	336	10	369
missense	11	71	556	129	11	778
nonsense	20	17	1			38
start loss		2	1			3
frameshift	38	24	4	2		68
inframe indel		4	7	1		12
splice donor/acceptor (+/-2bp)	5	24	1			30
splice region			13	17	2	32
non coding			123	96	121	340
Total	74	142	716	564	142

Highest pathogenic variant AF is 0.0000131

Variants in GRIN2A

This is a list of pathogenic ClinVar variants found in the GRIN2A region.

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

Position	Type	Phenotype	Significance	ClinVar
16-9753457-T-C		Landau-Kleffner syndrome	Benign (Jan 13, 2018)
16-9753517-A-T		Landau-Kleffner syndrome	Benign (Jan 13, 2018)
16-9753632-A-G		Landau-Kleffner syndrome	Benign (Jan 13, 2018)
16-9753668-A-T		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)
16-9753757-A-G		Landau-Kleffner syndrome	Uncertain significance (Jan 15, 2018)
16-9753824-C-G		Landau-Kleffner syndrome	Benign (Jan 13, 2018)
16-9753871-G-A		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)
16-9753894-G-C		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)
16-9753942-C-T		Landau-Kleffner syndrome	Uncertain significance (Jan 13, 2018)
16-9754171-C-G		Landau-Kleffner syndrome	Benign (Jan 12, 2018)
16-9754368-C-T		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)
16-9754396-A-G		Landau-Kleffner syndrome	Benign (Jan 13, 2018)
16-9754435-A-G		Landau-Kleffner syndrome	Benign (Jan 12, 2018)
16-9754523-C-G		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)
16-9754540-G-A		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)
16-9754607-A-G		Landau-Kleffner syndrome	Uncertain significance (Jun 14, 2016)
16-9754612-T-TG		Landau-Kleffner syndrome	Likely benign (Jun 14, 2016)
16-9754614-T-G		Landau-Kleffner syndrome	Benign (Jan 13, 2018)
16-9754751-C-T		Landau-Kleffner syndrome	Conflicting classifications of pathogenicity (Jul 01, 2023)
16-9754753-A-G		Landau-Kleffner syndrome	Benign (Apr 01, 2023)
16-9754786-GA-G			Likely benign (Jun 01, 2023)
16-9754790-A-G		Landau-Kleffner syndrome	Uncertain significance (Jan 13, 2018)
16-9754993-T-C		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)
16-9755072-A-C		Landau-Kleffner syndrome	Benign (Jan 13, 2018)
16-9755098-T-G		Landau-Kleffner syndrome	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRIN2A	protein_coding	protein_coding	ENST00000396573	12	424236

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000155	125742	0	6	125748	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.83	599	828	0.723	0.0000523	9746
Missense in Polyphen		160	364.58	0.43886		4321
Synonymous	-2.42	412	354	1.16	0.0000263	2825
Loss of Function	5.94	4	48.8	0.0820	0.00000246	602

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000123	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000441	0.0000439
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:28105280). Sensitivity to glutamate and channel kinetics depend on the subunit composition; channels containing GRIN1 and GRIN2A have higher sensitivity to glutamate and faster kinetics than channels formed by GRIN1 and GRIN2B (PubMed:26919761, PubMed:26875626). Contributes to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning (By similarity). {ECO:0000250|UniProtKB:P35436, ECO:0000250|UniProtKB:Q00959, ECO:0000269|PubMed:26875626, ECO:0000269|PubMed:26919761, ECO:0000269|PubMed:28105280, ECO:0000269|PubMed:8768735}.
• Disease: DISEASE: Epilepsy, focal, with speech disorder and with or without mental retardation (FESD) [MIM:245570]: A highly variable neurologic disorder with features ranging from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and mental retardation to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. The disorder encompasses several clinical entities, including Landau-Kleffner syndrome, epileptic encephalopathy with continuous spike and wave during slow-wave sleep, autosomal dominant rolandic epilepsy, mental retardation and speech dyspraxia, and benign epilepsy with centrotemporal spikes. {ECO:0000269|PubMed:20890276, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23933818, ECO:0000269|PubMed:23933819, ECO:0000269|PubMed:23933820, ECO:0000269|PubMed:24504326, ECO:0000269|PubMed:24903190, ECO:0000269|PubMed:27839871, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:28095420, ECO:0000269|PubMed:28126851, ECO:0000269|PubMed:28182669}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving GRIN2A has been found in a family with epilepsy and neurodevelopmental defects. Translocation t(16;17)(p13.2;q11.2).; DISEASE: Note=GRIN2A somatic mutations have been frequently found in cutaneous malignant melanoma, suggesting that the glutamate signaling pathway may play a role in the pathogenesis of melanoma. {ECO:0000269|PubMed:21499247, ECO:0000269|PubMed:24455489}.
• 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);Nicotine addiction - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Calcium signaling pathway - 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);Levomethadyl Acetate Action Action Pathway;Fluoxetine Action Pathway;Citalopram Action Pathway;Escitalopram Action Pathway;Imipramine Action Pathway;Desipramine Action Pathway;Levallorphan Action Pathway;Dimethylthiambutene Action Pathway;Ethylmorphine Action Pathway;Pentazocine Action Pathway;Naltrexone Action Pathway;Buprenorphine Action Pathway;Alvimopan Action Pathway;Naloxone Action Pathway;Dihydromorphine Action Pathway;Methadone Metabolism Pathway;Nicotine Action Pathway;Nalbuphine Action Pathway;Ketobemidone Action Pathway;Lidocaine (Local Anaesthetic) Action Pathway;Mepivacaine Action Pathway;Chloroprocaine Action Pathway;Cocaine Action Pathway;Dibucaine Action Pathway;Levobupivacaine Action Pathway;Benzocaine Action Pathway;Bupivacaine Action Pathway;Levorphanol Action Pathway;Propoxyphene Action Pathway;Tramadol Action Action Pathway;Diphenoxylate Action Pathway;Anileridine Action Pathway;Methadone Action Pathway;Oxycodone Action Pathway;Oxybuprocaine Action Pathway;Prilocaine Action Pathway;Procaine Action Pathway;Proparacaine Action Pathway;Ropivacaine Action Pathway;Codeine Action Pathway;Morphine Action Pathway;Heroin Action Pathway;Alfentanil Action Pathway;Oxymorphone Action Pathway;Hydrocodone Action Pathway;Hydromorphone Action Pathway;Sufentanil Action Pathway;Remifentanil Action Pathway;Fentanyl Action Pathway;Carfentanil Action Pathway;3-Methylthiofentanyl Action Pathway;Methadyl Acetate Action Pathway;Dezocine Action Pathway;Alzheimers Disease;Common Pathways Underlying Drug Addiction;NO-cGMP-PKG mediated Neuroprotection;Phosphodiesterases in neuronal function;Ras Signaling;Signal Transduction;nitric oxide signaling pathway;GPCR Dopamine D1like receptor;Neuronal System;Synaptic adhesion-like molecules;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Neurexins and neuroligins;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;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: 0.473

Intolerance Scores

• loftool: 0.0850
• rvis_EVS: -1.46
• rvis_percentile_EVS: 3.89

Haploinsufficiency Scores

• pHI: 0.379
• hipred: Y
• hipred_score: 0.843
• ghis: 0.587

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.838

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Grin2a
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); 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)

Gene ontology

• Biological process: MAPK cascade;startle response;response to amphetamine;glutamate receptor signaling pathway;chemical synaptic transmission;brain development;learning or memory;memory;visual learning;response to wounding;sensory perception of pain;calcium-mediated signaling;neurogenesis;sleep;directional locomotion;ionotropic glutamate receptor signaling pathway;negative regulation of protein catabolic process;dopamine metabolic process;serotonin metabolic process;positive regulation of apoptotic process;response to ethanol;regulation of synaptic plasticity;regulation of sensory perception of pain;excitatory postsynaptic potential;long-term synaptic potentiation;activation of cysteine-type endopeptidase activity;calcium ion transmembrane import into cytosol;excitatory chemical synaptic transmission;positive regulation of long-term synaptic potentiation;protein localization to postsynaptic membrane;cellular response to amyloid-beta
• Cellular component: endoplasmic reticulum;plasma membrane;integral component of plasma membrane;synaptic vesicle;cell surface;postsynaptic density;NMDA selective glutamate receptor complex;cell junction;presynaptic membrane;neuron projection;synaptic membrane;postsynaptic density membrane;glutamatergic synapse;integral component of postsynaptic density membrane
• Molecular function: amyloid-beta binding;NMDA glutamate receptor activity;Ras guanyl-nucleotide exchange factor activity;protein binding;zinc ion binding;glutamate-gated calcium ion channel activity