GRIN2D

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

Basic information

Region (hg38): 19:48393668-48444931

Previous symbols: [ "NMDAR2D" ]

Links

ENSG00000105464

∙ NCBI:2906 ∙ OMIM:602717 ∙ HGNC:4588 ∙ Uniprot:O15399 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

developmental and epileptic encephalopathy, 46 (Strong), mode of inheritance: AD
undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
developmental and epileptic encephalopathy, 46 (Strong), mode of inheritance: AD
complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
developmental and epileptic encephalopathy, 46 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 46	AD	Neurologic	The condition involves severe epileptic encephalopathy, and medical management (with NMDA receptor channel blockers) has been reported as effective as adjuvant epilepsy therapy	Neurologic	27616483

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRIN2D gene.

not_provided (1150 variants)
Inborn_genetic_diseases (150 variants)
Developmental_and_epileptic_encephalopathy,_46 (91 variants)
GRIN2D-related_disorder (38 variants)
not_specified (27 variants)
Intellectual_disability (8 variants)
See_cases (4 variants)
Seizure (1 variants)
Developmental_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRIN2D gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000836.4. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	374 clinvar	17 clinvar	398
missense	5 clinvar	16 clinvar	649 clinvar	49 clinvar	1 clinvar	720
nonsense			7 clinvar			7
start loss			1			1
frameshift			22 clinvar			22
splice donor/acceptor (+/-2bp)			3 clinvar		1 clinvar	4
Total	5	16	689	423	19

Highest pathogenic variant AF is 0.00000547259

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRIN2D	protein_coding	protein_coding	ENST00000263269	12	50057

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000352	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.85	266	600	0.443	0.0000410	8337
Missense in Polyphen		95	289.56	0.32809		2984
Synonymous	2.11	235	280	0.839	0.0000212	2970
Loss of Function	5.39	2	37.8	0.0529	0.00000197	449

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000881	0.0000881
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000619	0.0000615
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
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:9489750, PubMed:27616483, PubMed:26875626, PubMed:28126851). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:9489750). {ECO:0000269|PubMed:26875626, ECO:0000269|PubMed:27616483, ECO:0000269|PubMed:28095420, ECO:0000269|PubMed:28126851, ECO:0000269|PubMed:9489750}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 46 (EIEE46) [MIM:617162]: 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:27616483}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Long-term potentiation - Homo sapiens (human);Glutamatergic synapse - 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);Amphetamine addiction - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Alzheimers Disease;Serotonin and anxiety-related events;NO-cGMP-PKG mediated Neuroprotection;Phosphodiesterases in neuronal function;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 (Consensus)

Recessive Scores

pRec: 0.146

Haploinsufficiency Scores

pHI: 0.319
hipred: Y
hipred_score: 0.740
ghis: 0.634

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.632

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Grin2d
Phenotype: skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); 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); homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan);

Gene ontology

Biological process: startle response;brain development;adult locomotory behavior;calcium-mediated signaling;ionotropic glutamate receptor signaling pathway;regulation of synaptic plasticity;regulation of sensory perception of pain;excitatory postsynaptic potential;long-term synaptic potentiation;calcium ion transmembrane import into cytosol;excitatory chemical synaptic transmission
Cellular component: plasma membrane;integral component of plasma membrane;NMDA selective glutamate receptor complex;cell junction;postsynaptic density membrane
Molecular function: ionotropic glutamate receptor activity;NMDA glutamate receptor activity;protein binding;glutamate-gated calcium ion channel activity