GRIN2B

Chr 12

glutamate ionotropic receptor NMDA type subunit 2B

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

NCBI Gene: 2904 ENSG00000273079 UniProt: Q13224

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.

GeneReviews 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]

GeneReviews ResearchGenerating clinical summary…

GOF/LOFmechanismLOEUF 0.06

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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ClinVar Variants

282 unique Pathogenic / Likely Pathogenic· 579 VUS of 1820 total submissions

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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 →

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GeneReview available — GRIN2B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 · 42% of P/LP variants are LoF · 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

ClinVar Variant Classifications

1820 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic113

Likely Pathogenic169

VUS579

Likely Benign661

Benign143

Conflicting131

113

Pathogenic

169

Likely Pathogenic

579

VUS

661

Likely Benign

143

Benign

131

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	78	31	4	0	113
Likely Pathogenic	40	129	0	0	169
VUS	10	539	18	12	579
Likely Benign	0	68	127	466	661
Benign	0	74	46	23	143
Conflicting	—				131
Total	128	841	195	501	1,796

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

51 pathogenic / likely-pathogenic (of 60) ClinVar copy-number / structural variants overlap GRIN2B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →