STXBP1

protein-coding

syntaxin binding protein 1

Gene summary

This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MANE transcript

NM_001032221.6

Inheritance

AD, AR

ClinVar variants

P:400U:264B:251

Top phenotype

Developmental and epileptic encephalopathy 4

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr9:127,579,370-127,696,027

External References & Databases

Ensembl (ENSG00000136854)

Transcript & Mutation Effects

hg38 • Region Span ~116.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

**Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from infantile epilepsy syndrome to developmental and epileptic encephalopathy. The evidence summary below reflects this change. The original evidence and conclusion remains the same; therefore, the original date of approval has not been changed. ** Approved by the ClinGen Epilepsy Expert Panel 10/20/2017.

atypical Rett syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017746

Submitter: Orphanet

Dravet syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011794

Submitter: Orphanet

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

developmental and epileptic encephalopathy, 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012812

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012812

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012812

Submitter: G2P

autism spectrum disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Ambry Genetics

intellectual disabilityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012812

Submitter: Labcorp Genetics (formerly Invitae)

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 4AD

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

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 18469812; 18065176; 19557857; 20876469; 21062273; 21376300; 21762454; 21770924; 22596016; 23020937; 24623842

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STXBP1 variants in ClinVar

50 Conditions Cataloged

Early-infantile DEETotal: 743

not providedTotal: 392

Developmental and epileptic encephalopathy, 4Total: 249

not specifiedTotal: 108

Inborn genetic diseasesTotal: 106

Infantile epilepsy syndromeTotal: 42

STXBP1-related disorderTotal: 28

Developmental and epileptic encephalopathyTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001032221.6. 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	3 clinvar	5 clinvar	170 clinvar	8 clinvar	187
missense	51 clinvar	98 clinvar	252 clinvar	59 clinvar	14 clinvar	474
nonsense	57 clinvar	3 clinvar				60
start loss		1 clinvar	2 clinvar			3
frameshift	93 clinvar	16 clinvar	3 clinvar			112
splice donor/acceptor (+/-2bp)	56 clinvar	21 clinvar	2 clinvar			79
Total	258	142	264	229	22	915

Highest pathogenic variant AF is 0.000027881317

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001032221.6	RefSeq	NP_001027392.1	19	MANE Select
ENST00000373299.5	Ensembl	ENSP00000362396.2	19	MANE Select
NM_001374306.2	RefSeq	NP_001361235.1	19	Standard
NM_001374307.2	RefSeq	NP_001361236.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
stxbp1b	Danio rerio	Structure: whole organism Quality: increased pigmentation abnormal

Gene / Model

Organism

Observed Phenotype

stxbp1b

Danio rerio

Structure: whole organism

Quality: increased pigmentation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Synaptic Vesicle Pathway
EGF-EGFR Signaling Pathway
Insulin Signaling
Effects of Botulinum toxin

Biological Process

platelet degranulation
developmental process involved in reproduction
vesicle docking involved in exocytosis
neuromuscular synaptic transmission
axon target recognition

Molecular Function

SNARE binding
RNA binding
protein binding
syntaxin-1 binding
protein kinase binding

Cellular Component

nucleoplasm
cytoplasm
mitochondrion
cytosol
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373302
Coding exons: 19
Length: 82917
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125695
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.26	127	352	0.361	0.0000235	3991
Missense (PolyPhen)		35	113.74	0.30773		1348
Synonymous	0.963	122	136	0.895	0.00000948	1139
Loss of Function	5.46	0	34.7	0.00	0.00000185	410

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May participate in the regulation of synaptic vesicle docking and fusion, possibly through interaction with GTP-binding proteins. Essential for neurotransmission and binds syntaxin, a component of the synaptic vesicle fusion machinery probably in a 1:1 ratio. Can interact with syntaxins 1, 2, and 3 but not syntaxin 4. May play a role in determining the specificity of intracellular fusion reactions.;

Recessive Scores

pRec: 0.221

Intolerance Scores

LoFtool: 0.0349
RVIS EVS: -0.69
RVIS percentile EVS: 14.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.754

Gene Damage Prediction

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