GeneBe

GRIN2D

protein-coding

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

Gene summary

N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors. NMDA channel has been shown to be involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. NMDA receptor channels are heteromers composed of the key receptor subunit NMDAR1 (GRIN1) and 1 or more of the 4 NMDAR2 subunits: NMDAR2A (GRIN2A), NMDAR2B (GRIN2B), NMDAR2C (GRIN2C), and NMDAR2D (GRIN2D). [provided by RefSeq, Mar 2010]

Previous symbols:
  • NMDAR2D

MANE transcript

NM_000836.4

Inheritance

AD

ClinVar variants

P:20U:784B:496

Top phenotype

Developmental and epileptic encephalopathy 46

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr19:48,393,668-48,444,931

External References & Databases

Ensembl (ENSG00000105464)NCBI Gene (2906)OMIM (602717)HGNC:4588GenCCUniProt (O15399)AlphaFoldClinVar (GRIN2D)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~51.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 46STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014947

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Variants in *GRIN2D* were first reported in individuals with autosomal dominant global developmental delay and seizures in 2016 (Li et al., PMID: 27616483). Since then, many individuals have been reported with variants in *GRIN2D*, generally presenting with various seizure types, developmental delays, and muscle tone or movement abnormalities within the first year of life. Individuals frequently present with cerebral atrophy as well. For this reason, the Epilepsy GCEP has decided to curate variants in *GRIN2D* under the disease term complex neurodevelopmental disorder (MONDO:0100038). Twelve missense variants that have been reported in 16 probands in 6 publications (PMIDs: 27616483, 30280376, 31504254, 32860008, 33397303, 33482465) are included in this curation. The mechanism of pathogenicity appears to be both loss- and gain-of-function (PMIDs: 35228668, 27616483). This gene-disease relationship is also supported by experimental evidence including in vitro functional assays and protein interaction studies (PMIDs: 18779583, 31504254 35228668). Disease-causing variants may show decreased receptor surface expression, either enhanced or reduced sensitivity to agonists, and altered channel open probability. In summary, *GRIN2D* has a definitive relationship 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 gene-disease pair was originally evaluated by the Epilepsy Gene Curation Expert Panel on July 3, 2018. It was re-evaluated on March 15, 2022. As a result of this reevaluation, the classification changed from Limited to Definitive due to publication of additional patients. This curation also underwent an administrative update on January 4, 2023 in which the disease term was changed from developmental and epileptic encephalopathy to a broader term, complex neurodevelopmental disorder. No new evidence has been reviewed or added.

developmental and epileptic encephalopathy, 46STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014947

Submitter: G2P

developmental and epileptic encephalopathy, 46STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014947

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 46STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014947

Submitter: Labcorp Genetics (formerly Invitae)

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 46AD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: The condition involves severe epileptic encephalopathy, and medical management (with NMDA receptor channel blockers) has been reported as effective as adjuvant epilepsy therapy

Refs: 27616483Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRIN2D variants in ClinVar

12 Conditions Cataloged
not providedTotal: 1268
Inborn genetic diseasesTotal: 174
not specifiedTotal: 123
Developmental and epileptic encephalopathy, 46Total: 104
GRIN2D-related disorderTotal: 52
Intellectual disabilityTotal: 8
See casesTotal: 4
Complex neurodevelopmental disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000836.4. 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
11
clinvar
428
clinvar
8
clinvar
 447
missense
4
clinvar
16
clinvar
735
clinvar
59
clinvar
1
clinvar
 815
nonsense
10
clinvar
 10
start loss
1
clinvar
 1
frameshift
24
clinvar
 24
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total41678448791300
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000836.4RefSeqNP_000827.212MANE Select
ENST00000263269.4EnsemblENSP00000263269.212MANE Select
ENST00000911262.1EnsemblENSP00000581321.112Standard
ENST00000911262.2EnsemblENSP00000581321.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

Biological Process

  • startle response
  • brain development
  • adult locomotory behavior
  • calcium-mediated signaling
  • ionotropic glutamate receptor signaling pathway

Molecular Function

  • ionotropic glutamate receptor activity
  • NMDA glutamate receptor activity
  • protein binding
  • glutamate-gated calcium ion channel activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • NMDA selective glutamate receptor complex
  • cell junction
  • postsynaptic density membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000263269
Coding exons
12
Length
50057
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125748
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.852666000.4430.00004108337
Missense (PolyPhen)95289.560.328092984
Synonymous2.112352800.8390.00002122970
Loss of Function5.39237.80.05290.00000197449

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000880.000087rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000620.000062rare
South Asian0.0000330.000033rare
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: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.;

Recessive Scores

pRec
0.146

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.632

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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