GeneBe

STXBP2

protein-coding

syntaxin binding protein 2

Gene summary

This gene encodes a member of the STXBP/unc-18/SEC1 family. The encoded protein is involved in intracellular trafficking, control of SNARE (soluble NSF attachment protein receptor) complex assembly, and the release of cytotoxic granules by natural killer cells. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2013]

MANE transcript

NM_006949.4

Inheritance

AR, AD

ClinVar variants

P:110U:374B:314

Top phenotype

Hemophagocytic lymphohistiocytosis, familial 5, with or without microvillous inclusion disease

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr19:7,636,772-7,647,873

External References & Databases

Ensembl (ENSG00000076944)NCBI Gene (6813)OMIM (601717)HGNC:11445GenCCUniProt (Q15833)AlphaFoldClinVar (STXBP2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial hemophagocytic lymphohistiocytosis 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013135

Submitter: ClinGen

*STXBP2* was first reported in relation to autosomal recessive familial hemophagocytic lymphohistiocytosis 5 (FHL5) in 2009 (zur Stadt U, et al., 2009, PMID: 19804848). FHL is a hyperinflammatory syndrome caused by an uncontrolled and ineffective proliferation and activation of T lymphocytes, natural killer (NK) cells, and macrophages that infiltrate multiple organs, including liver, spleen, lymph nodes, and central nervous system (CNS), and produce massive amounts of cytokines. This overwhelming hyperimmune status results in a clinical picture characterized by persistent fever, hepatosplenomegaly, pancytopenia, hemophagocytosis in various tissues, coagulation abnormalities, and inflammatory CNS disease. Patients with FHL5 have several unique features, including sensorineural hearing deficit, abnormal bleeding, and severe diarrhea. *STXBP2* is involved in intracellular vesicle trafficking and vesicle fusion with membranes, it contributes to the granule exocytosis machinery through interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins that regulate membrane fusion. The role of *STXBP2* in the cytotoxic granule pathway, and how variation in the gene results in FHL5 is currently not understood in detail but the mechanism of disease appears to be loss of function. This curation includes eleven variants (including in-frame deletions, missense, splicing, and frameshift) found in ten probands from two publications (PMIDs: 19804848, 22451424). Additional cases are available in the literature however the maximum score for genetic evidence has been reached. A role in disease is supported by increased expression of *STXBP2* in NK cells, T cells, monocytes, and other hematopoietic cells (PMID: 19804848), which is altered in patients (PMID: 19884660), resulting in altered cytotoxicity of patient NK cells and cytotoxic T-lymphocytes (PMID: 19804848). Additionally, degranulation defects were rescued in patient cells with wildtype *STXBP2* (PMID: 19884660). *STXBP2* is also known to interact with *STX11*, which has a well established relationship with FHL (PMID: 19804848). In summary *STXBP2* is definitively associated with autosomal recessive FHL5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

hereditary hemophagocytic lymphohistiocytosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015541

Submitter: Orphanet

familial hemophagocytic lymphohistiocytosis 5LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013135

Submitter: Ambry Genetics

familial hemophagocytic lymphohistiocytosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013135

Submitter: Labcorp Genetics (formerly Invitae)

microvillus inclusion diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009635

Submitter: Ambry Genetics

familial hemophagocytic lymphohistiocytosis 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013135

Submitter: Ambry Genetics

familial hemophagocytic lymphohistiocytosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013135

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hemophagocytic lymphohistiocytosis, familial 5, with or without microvillous inclusion diseaseAR

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal; Neurologic

Intervention: Allergy/Immunology/Infectious; Gastrointestinal

Rationale: Antibiotics or antiviral agents can be beneficial to treat/prevent infections that can trigger an exaggerated inflammatory response; The condition can involve hematologic manifestations as well as enteropathy, and awareness may allow medical (eg, with anti-interferon-gamma antibody and corticosteroids) and nutritional interventions related to the sequelae; Chemo/immunotherapy can achieve clinical stability prior to allogeneic hematopoietic cell transplantation (HCT), the only curative therapy.

Refs: 19804848; 19884660; 20798128; 23382066; 29266534; 32374962Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STXBP2 variants in ClinVar

10 Conditions Cataloged
Familial hemophagocytic lymphohistiocytosis 5Total: 1123
not specifiedTotal: 153
not providedTotal: 133
Inborn genetic diseasesTotal: 81
STXBP2-related disorderTotal: 81
Autoinflammatory syndromeTotal: 35
Familial hemophagocytic lymphohistiocytosisTotal: 14
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITHOUT MICROVILLUS INCLUSION DISEASETotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006949.4. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
288
clinvar
1
clinvar
 298
missense
3
clinvar
15
clinvar
357
clinvar
25
clinvar
 400
nonsense
17
clinvar
8
clinvar
3
clinvar
 28
start loss
0
frameshift
22
clinvar
14
clinvar
1
clinvar
 37
splice donor/acceptor (+/-2bp)
2
clinvar
29
clinvar
4
clinvar
 35
Total44663743131798

Highest pathogenic variant AF is 0.00033532793

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006949.4RefSeqNP_008880.219MANE Select
ENST00000221283.10EnsemblENSP00000221283.419MANE Select
NM_001127396.3RefSeqNP_001120868.119Standard
NM_001272034.2RefSeqNP_001258963.119Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Splicing factor NOVA regulated synaptic proteins
  • Insulin Signaling
  • Other interleukin signaling
  • Signaling by Interleukins
  • Cytokine Signaling in Immune system

Biological Process

  • leukocyte mediated cytotoxicity
  • platelet degranulation
  • vesicle docking involved in exocytosis
  • protein transport
  • regulation of mast cell degranulation

Molecular Function

  • protein binding
  • syntaxin-1 binding
  • syntaxin-3 binding

Cellular Component

  • extracellular region
  • cytosol
  • plasma membrane
  • apical plasma membrane
  • specific granule

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000221283
Coding exons
19
Length
10993
Individuals with no LoFs
125716
Homozygous LoFs
0
Heterozygous LoFs
32
Defined
125748
p
0.000127
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.4813443700.9300.00002563831
Missense (PolyPhen)120134.260.893781559
Synonymous-1.151801611.110.00001221178
Loss of Function2.241730.30.5610.00000132385

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.000150.00014rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000470.000046rare
European (Non-Finnish)0.000160.00016rare
South Asian0.000160.00016rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in intracellular vesicle trafficking and vesicle fusion with membranes. Contributes to the granule exocytosis machinery through interaction with soluble N- ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that regulate membrane fusion. Regulates cytotoxic granule exocytosis in natural killer (NK) cells. {ECO:0000269|PubMed:19804848, ECO:0000269|PubMed:19884660}.;

Recessive Scores

pRec
0.132

Intolerance Scores

LoFtool
0.607
RVIS EVS
0.43
RVIS percentile EVS
77.29

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.781

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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