GRID2

protein-coding

glutamate ionotropic receptor delta type subunit 2, the group of Glutamate ionotropic receptor delta type subunits

Gene summary

The protein encoded by this gene is a member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain. The encoded protein is a multi-pass membrane protein that is expressed selectively in cerebellar Purkinje cells. A point mutation in the mouse ortholog, associated with the phenotype named 'lurcher', in the heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis. This protein also plays a role in synapse organization between parallel fibers and Purkinje cells. Alternate splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause cerebellar ataxia in humans. [provided by RefSeq, Apr 2014]

MANE transcript

NM_001510.4

Inheritance

AR, AD

ClinVar variants

P:10U:187B:78

Top phenotype

Spinocerebellar ataxia, autosomal recessive 18

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr4:92,303,966-93,810,157

External References & Databases

Ensembl (ENSG00000152208)

Transcript & Mutation Effects

hg38 • Region Span ~1,506.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spinocerebellar ataxia 18SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014530

Submitter: Orphanet

autosomal recessive spinocerebellar ataxia 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014530

Submitter: G2P

autosomal recessive spinocerebellar ataxia 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014530

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive spinocerebellar ataxia 18STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014530

Submitter: G2P

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 18AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23611888; 24078737

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRID2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 192

Inborn genetic diseasesTotal: 119

not specifiedTotal: 21

Autosomal recessive spinocerebellar ataxia 18Total: 17

GRID2-related disorderTotal: 10

See casesTotal: 2

GRID2-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001510.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	63 clinvar	7 clinvar	71
missense	1 clinvar	4 clinvar	186 clinvar	7 clinvar	1 clinvar	199
nonsense	1 clinvar	4 clinvar				5
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	2	8	187	70	8	275

Highest pathogenic variant AF is 0.0000065844056

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001510.4	RefSeq	NP_001501.2	16	MANE Select
ENST00000282020.9	Ensembl	ENSP00000282020.4	16	MANE Select
NM_001286838.1	RefSeq	NP_001273767.1	15	Standard
NM_001440459.1	RefSeq	NP_001427388.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Long-term depression - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)

Biological Process

heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules
glutamate receptor signaling pathway
regulation of neuron projection development
cerebellar granule cell differentiation
ion transmembrane transport

Molecular Function

ionotropic glutamate receptor activity
protein binding
glutamate receptor activity
PDZ domain binding
scaffold protein binding

Cellular Component

plasma membrane
integral component of plasma membrane
ionotropic glutamate receptor complex
cell junction
dendritic spine

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282020
Coding exons: 16
Length: 1470158
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125748
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.708	527	575	0.917	0.0000317	6604
Missense (PolyPhen)		177	234.83	0.75373		2618
Synonymous	-1.07	229	209	1.09	0.0000115	1993
Loss of Function	6.29	4	53.8	0.0744	0.00000322	549

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for glutamate. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. Promotes synaptogenesis and mediates the D-Serine- dependent long term depression signals and AMPA receptor endocytosis of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses through the beta-NRX1-CBLN1-GRID2 triad complex (PubMed:27418511). {ECO:0000269|PubMed:27418511}.;
Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 18 (SCAR18) [MIM:616204]: Spinocerebellar ataxia defines a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR18 features include progressive cerebellar atrophy, delayed psychomotor development, severely impaired gait, ocular movement abnormalities, and intellectual disability. {ECO:0000269|PubMed:23611888, ECO:0000269|PubMed:24078737, ECO:0000269|PubMed:25841024, ECO:0000269|PubMed:27418511}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.161

Intolerance Scores

LoFtool: 0.0371
RVIS EVS: -0.84
RVIS percentile EVS: 11.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.800

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium