GeneBe

GLRB

protein-coding

glycine receptor beta, the group of Glycine receptors

Gene summary

This gene encodes the beta subunit of the glycine receptor, which is a pentamer composed of alpha and beta subunits. The receptor functions as a neurotransmitter-gated ion channel, which produces hyperpolarization via increased chloride conductance due to the binding of glycine to the receptor. Mutations in this gene cause startle disease, also known as hereditary hyperekplexia or congenital stiff-person syndrome, a disease characterized by muscular rigidity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

MANE transcript

NM_000824.5

Inheritance

AR, AD

ClinVar variants

P:22U:180B:110

Top phenotype

Hyperekplexia 2

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr4:157,076,125-157,172,090

External References & Databases

Ensembl (ENSG00000109738)NCBI Gene (2743)OMIM (138492)HGNC:4329GenCCUniProt (P48167)AlphaFoldClinVar (GLRB)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~96.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperekplexia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013828

Submitter: G2P

hyperekplexia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013828

Submitter: Labcorp Genetics (formerly Invitae)

hyperekplexia 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013828

Submitter: G2P

hyperekplexia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013828

Submitter: PanelApp Australia

hereditary hyperekplexiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0021022

Submitter: Orphanet

hyperekplexia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013828

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hyperekplexia 2AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Neonates are at risk of sudden death from apnea/aspiration, and surveillance, as well as primary prevention with medical treatments (eg, clonazepam) may be beneficial

Refs: 11929858; 21391991; 20301437Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLRB variants in ClinVar

8 Conditions Cataloged
Hyperekplexia 2Total: 362
Inborn genetic diseasesTotal: 65
not providedTotal: 21
not specifiedTotal: 20
GLRB-related disorderTotal: 5
HypotoniaTotal: 1
GLRB-related disordersTotal: 1
SeizureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000824.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
98
clinvar
 100
missense
1
clinvar
1
clinvar
171
clinvar
10
clinvar
2
clinvar
 185
nonsense
5
clinvar
1
clinvar
2
clinvar
 8
start loss
1
clinvar
 1
frameshift
9
clinvar
2
clinvar
 11
splice donor/acceptor (+/-2bp)
3
clinvar
2
clinvar
2
clinvar
 7
Total1841801082312

Highest pathogenic variant AF is 0.000081312544

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000824.5RefSeqNP_000815.19MANE Select
ENST00000264428.9EnsemblENSP00000264428.49MANE Select
NM_001166060.2RefSeqNP_001159532.19Standard
NM_001166061.2RefSeqNP_001159533.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
glrbbDanio rerio

Structure: trunk

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • Neuronal System
  • Neurotransmitter receptors and postsynaptic signal transmission
  • Transmission across Chemical Synapses

Biological Process

  • startle response
  • ion transport
  • signal transduction
  • neuropeptide signaling pathway
  • chemical synaptic transmission

Molecular Function

  • transmembrane signaling receptor activity
  • extracellular ligand-gated ion channel activity
  • chloride channel activity
  • protein binding
  • glycine binding

Cellular Component

  • cytoplasm
  • plasma membrane
  • integral component of plasma membrane
  • glycine-gated chloride channel complex
  • cell junction

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264428
Coding exons
9
Length
96034
Individuals with no LoFs
125724
Homozygous LoFs
0
Heterozygous LoFs
22
Defined
125746
p
0.0000875
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8302202570.8540.00001243260
Missense (PolyPhen)73106.220.687221352
Synonymous0.9668395.00.8740.00000488941
Loss of Function2.80923.70.3800.00000128295

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000100.000099rare
East Asian0.0000550.000054rare
Finnish00.0absent
European (Non-Finnish)0.000110.00011rare
South Asian0.0000650.000065rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Glycine receptors are ligand-gated chloride channels. GLRB does not form ligand-gated ion channels by itself, but is part of heteromeric ligand-gated chloride channels. Channel opening is triggered by extracellular glycine (PubMed:8717357, PubMed:15302677, PubMed:16144831, PubMed:22715885, PubMed:25445488, PubMed:11929858, PubMed:23238346). Heteropentameric channels composed of GLRB and GLRA1 are activated by lower glycine levels than homopentameric GLRA1 (PubMed:8717357). Plays an important role in the down-regulation of neuronal excitability (PubMed:11929858, PubMed:23238346). Contributes to the generation of inhibitory postsynaptic currents (PubMed:25445488). {ECO:0000269|PubMed:11929858, ECO:0000269|PubMed:15302677, ECO:0000269|PubMed:16144831, ECO:0000269|PubMed:22715885, ECO:0000269|PubMed:23238346, ECO:0000269|PubMed:25445488, ECO:0000269|PubMed:8717357}.;
Disease
DISEASE: Hyperekplexia 2 (HKPX2) [MIM:614619]: A neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli. {ECO:0000269|PubMed:11929858, ECO:0000269|PubMed:21391991, ECO:0000269|PubMed:23238346}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.148

Intolerance Scores

LoFtool
0.342
RVIS EVS
-1
RVIS percentile EVS
8.32

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.837

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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