GRM8

protein-coding

glutamate metabotropic receptor 8, the group of MicroRNA protein coding host genes|Glutamate metabotropic receptors

Gene summary

L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000845.3

Inheritance

—

ClinVar variants

U:116B:32

Top phenotype

GRM8-related disorder

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr7:126,438,598-127,253,093

External References & Databases

Ensembl (ENSG00000179603)

Transcript & Mutation Effects

hg38 • Region Span ~814.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRM8 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 105

not providedTotal: 35

GRM8-related disorderTotal: 12

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000845.3. 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				16 clinvar	6 clinvar	22
missense			111 clinvar	5 clinvar	5 clinvar	121
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	116	21	11	148

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000845.3	RefSeq	NP_000836.2	10	MANE Select
ENST00000339582.7	Ensembl	ENSP00000344173.2	10	MANE Select
NM_001127323.1	RefSeq	NP_001120795.1	9	Standard
NM_001371083.1	RefSeq	NP_001358012.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glutamatergic synapse - Homo sapiens (human)
Phospholipase D signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
GPCRs, Other
GPCRs, Class C Metabotropic glutamate, pheromone

Biological Process

G protein-coupled receptor signaling pathway
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway
adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway
G protein-coupled glutamate receptor signaling pathway
visual perception

Molecular Function

G protein-coupled receptor activity
glutamate receptor activity

Cellular Component

plasma membrane
integral component of plasma membrane
presynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000339582
Coding exons: 10
Length: 814697
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.914	464	523	0.887	0.0000287	5953
Missense (PolyPhen)		207	259.35	0.79816		2814
Synonymous	-0.546	202	192	1.05	0.0000110	1794
Loss of Function	3.42	18	41.9	0.430	0.00000265	444

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000055	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000098	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:9473604}.;

Recessive Scores

pRec: 0.187

Intolerance Scores

LoFtool: 0.0291
RVIS EVS: -0.57
RVIS percentile EVS: 19.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.125

Gene Damage Prediction

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