GRIN2A

Chr 16AD

glutamate ionotropic receptor NMDA type subunit 2A

Also known as: EPND, FESD, GluN2A, LKS, NMDAR2A, NR2A

NCBI Gene: 2903 ENSG00000183454 UniProt: Q12879 OMIM: 138253

The encoded protein is an N-methyl-D-aspartate (NMDA) receptor subunit that forms ligand-gated and voltage-dependent ion channels permeable to calcium, mediating synaptic transmission and long-term potentiation essential for memory and learning. Mutations cause autosomal dominant focal epilepsy with speech disorder and with or without intellectual disability. The gene is highly intolerant to loss-of-function variants, suggesting mutations can cause disease through multiple mechanisms including haploinsufficiency for truncating variants and potentially dominant-negative or gain-of-function effects for specific missense variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOF/LOFmechanismADLOEUF 0.191 OMIM phenotype

VCEP Guidelines: GRIN DisordersPilot

ClinGen Panel

Clinical Summary— GRIN2A

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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

67 unique Pathogenic / Likely Pathogenic· 241 VUS of 500 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 — GRIN2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.19LOEUF

pLI 1.000

Z-score 5.94

OE 0.08 (0.04–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.83Z-score

OE missense 0.72 (0.68–0.77)

599 obs / 828.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.08 (0.04–0.19)

0≤0.351.4

Missense OE0.72 (0.68–0.77)

0≤0.61.4

Synonymous OE1.16

0≤1.21.6

LoF obs/exp: 4 / 48.8Missense obs/exp: 599 / 828.0Syn Z: -2.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedGRIN2A-related neurodevelopmental disorderOTHERAR

definitiveGRIN2A-related epilepsy, focal, with speech disorder, and with or without intellectual developmental disorderLOFAD

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

NMDA receptor GluN2A subunit. GOF variants (prolonged deactivation, increased charge transfer) cause DEE. LOF variants cause epilepsy-aphasia spectrum. Mechanism is variant-specific.

References:PMID:29691073

0.5576th %ile

GOF

0.6345th %ile

LOF

0.62top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 60% of P/LP variants are LoF · LOEUF 0.19

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNSomatic mutation of GRIN2A results in a dominant negative effect inhibiting the tumor-suppressive phenotype of wild-type (WT) GRIN2A in melanoma.PMID:24739903

LOFThe present identification of heterozygous GRIN2A deletions and of a splice-site, frameshift mutation in individuals with LKS, CSWSS or atypical rolandic epilepsy predicted haploinsufficiency effects.PMID:23933820

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