GRIN2C

Chr 17

glutamate ionotropic receptor NMDA type subunit 2C

Also known as: GluN2C, NMDAR2C, NR2C

NCBI Gene: 2905 ENSG00000161509 UniProt: Q14957 OMIM: 138254

The encoded protein is the GluN2C subunit of NMDA receptors, which form calcium-permeable ion channels essential for synaptic plasticity, learning, and memory in the central nervous system. Mutations cause autosomal dominant intellectual disability with early-onset seizures and developmental delay. This gene shows very high constraint against loss-of-function variants (pLI near 0, LOEUF 0.715), indicating that heterozygous mutations are likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a subunit of the N-methyl-D-aspartate (NMDA) receptor, which is a subtype of ionotropic glutamate receptor. NMDA receptors are found in the central nervous system, are permeable to cations and have an important role in physiological processes such as learning, memory, and synaptic development. The receptor is a tetramer of different subunits (typically heterodimer of subunit 1 with one or more of subunits 2A-D), forming a channel that is permeable to calcium, potassium, and sodium, and whose properties are determined by subunit composition. Alterations in the subunit composition of the receptor are associated with pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, depression, and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.71

Clinical Summary— GRIN2C

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

154 VUS of 194 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 2.89

OE 0.48 (0.33–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.61Z-score

OE missense 0.82 (0.76–0.88)

519 obs / 633.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.33–0.71)

0≤0.351.4

Missense OE?0.82 (0.76–0.88)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 17 / 35.6Missense obs/exp: 519 / 633.0Syn Z: 0.69

This gene — mechanism propensity

0.74top 25%

GOF

0.75top 25%

LOF

0.3453th %ile

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

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

194 submitted variants in ClinVar

ClinVar

Classification Summary

VUS154

Likely Benign20

Benign6

Conflicting1

154

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	153	0	0	154
Likely Benign	0	11	1	8	20
Benign	0	2	2	2	6
Conflicting	—				1
Total	1	166	3	10	181

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap GRIN2C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →