GRIN2B

Chr 12AD

glutamate ionotropic receptor NMDA type subunit 2B

Also known as: DEE27, EIEE27, GluN2B, MRD6, NMDAR2B, NR2B, NR3, hNR3

NCBI Gene: 2904 ENSG00000273079 UniProt: Q13224 OMIM: 138252

The protein functions as the GluN2B subunit of NMDA receptors, forming heterotetrameric calcium-permeable ion channels that bind glutamate and mediate excitatory synaptic transmission critical for synaptic plasticity, learning, and memory. Autosomal dominant mutations cause developmental and epileptic encephalopathy 27 and intellectual developmental disorder with or without seizures, predominantly through loss-of-function mechanisms. The gene shows extreme intolerance to loss-of-function variants, consistent with haploinsufficiency as a primary disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

GOF/LOFmechanismADLOEUF 0.062 OMIM phenotypes

VCEP Guidelines: GRIN DisordersPilot

ClinGen Panel

Clinical Summary— GRIN2B

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 6.48

OE 0.00 (0.00–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.42Z-score

OE missense 0.48 (0.44–0.52)

415 obs / 862.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.06)

0≤0.351.4

Missense OE?0.48 (0.44–0.52)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 0 / 48.9Missense obs/exp: 415 / 862.7Syn Z: -2.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGRIN2B-related epileptic encelopathyOTHERAD

definitiveGRIN2B-related intellectual developmental disorderLOFAD

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

NMDA receptor GluN2B subunit. GOF variants in TM/linker regions cause severe DEE. LOF variants cause ID without epilepsy. G2P lists as undetermined/LOF but GOF is well-established for DEE variants.1

This gene — mechanism propensity

0.4289th %ile

GOF

0.5856th %ile

LOF

0.74top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.06 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

Literature Evidence

GOFWe identified GRIN2B gain-of-function mutations as a cause of West syndrome with severe developmental delay as well as of ID with childhood onset focal epilepsy.2

LOFMultiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References