GRIK2

Chr 6ARAD

glutamate ionotropic receptor kainate type subunit 2

Also known as: EAA4, GLR6, GLUK6, GLUR6, GluK2, MRT6, NEDLAS

NCBI Gene: 2898 ENSG00000164418 OMIM: 138244

This protein functions as an ionotropic glutamate receptor that forms cation-permeable channels gated by L-glutamate and kainic acid, serving as an excitatory neurotransmitter receptor in the central nervous system. Mutations cause intellectual developmental disorder and neurodevelopmental disorder with impaired language and ataxia with or without seizures, inherited in autosomal recessive or autosomal dominant patterns. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to the kainate family of glutamate receptors, which are composed of four subunits and function as ligand-activated ion channels. The subunit encoded by this gene is subject to RNA editing at multiple sites within the first and second transmembrane domains, which is thought to alter the structure and function of the receptor complex. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. Mutations in this gene have been associated with autosomal recessive cognitive disability. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.262 OMIM phenotypes

Clinical Summary— GRIK2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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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

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.998

Z-score 5.41

OE 0.13 (0.07–0.26)

Highly constrained

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

Missense Constraint?

2.91Z-score

OE missense 0.64 (0.58–0.70)

319 obs / 502.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.26)

0≤0.351.4

Missense OE?0.64 (0.58–0.70)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 6 / 45.2Missense obs/exp: 319 / 502.3Syn Z: -0.50

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGRIK2-related intellectual developmental disorderLOFAR

strongGRIK2-related intellectual disability and hypomyelinationOTHERAD

This gene — mechanism propensity

0.5771th %ile

GOF

0.7030th %ile

LOF

0.53top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). 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 · 1 literature citation

LOFLOEUF 0.26

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

GOFA gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits.1

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

References