SBF2

protein-coding

SET binding factor 2, the group of DENN domain containing|Myotubularins|Pleckstrin homology domain containing

Gene summary

This gene encodes a pseudophosphatase and member of the myotubularin-related protein family. This gene maps within the CMT4B2 candidate region of chromosome 11p15 and mutations in this gene have been associated with Charcot-Marie-Tooth Disease, type 4B2. [provided by RefSeq, Jul 2008]

Previous symbols:

CMT4B2

MANE transcript

NM_030962.4

Inheritance

ClinVar variants

P:97U:814B:418

Top phenotype

Charcot-Marie-Tooth disease, type 4B2

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr11:9,776,776-10,304,877

External References & Databases

Ensembl (ENSG00000133812)

Transcript & Mutation Effects

hg38 • Region Span ~528.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 4B2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011475

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 4B2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011475

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 4B2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011475

Submitter: G2P

Charcot-Marie-Tooth disease type 4B2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011475

Submitter: ClinGen

The linkage region of SBF2 on chromosome 11p15 was first reported in 1999 in association with autosomal recessive CMT with focally-folded myelin (PMID: 10644431). In 2003, an in-frame deletion in SBF2 was described (PMID: 12554688), followed by several stop (e.g. 12687498, 15304601), frame-shift (PMID: 25873783, 30028002), and splice variants (PMID: 15477569) all representing biallelic loss-of-function changes. The mutation spectrum was later enlarged by missense variants as well (PMID: 30028002), likewise leading to a childhood-onset CMT phenotype with slow nerve conduction velocities (~ 15m/s) and tomaculous myelin outfoldings. The loss-of function pathomechanism is supported by a SBF2 knockout mouse model (PMID: 17855448, 18349142, 23297362) well-reproducing phenotypic elements such as muscle weakness, poor motor performance, reduced nerve conduction velocities and delayed F-waves, as well as myelin folding abnormalities. SBF2 is expressed in the Schwann cell cytoplasm (PMID: 23297362) and interacts with MTMR2 (15998640, 23297362), a protein that is likewise associated with AR demyelinating CMT (CMT4B1). In summary, SBF2 is definitively associated with autosomal recessive demyelinating Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.

Charcot-Marie-Tooth disease type 4B2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011475

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease type 4B2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011475

Submitter: Orphanet

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, type 4B2AR

Manifestation: Audiologic/Otolaryngologic; Neurologic; Ophthalmologic

Intervention: Ophthalmologic; Pharmacogenomic

Rationale: Open-angle glaucoma is typically asymptomatic until late stages, when irreversible nerve damage has already taken place; As the condition may include early-onset hearing loss, intervention related to speech and language development may be beneficial; Agents that may contribute to glaucoma should be avoided

Comments: Several families with CMT4B2 with early-onset glaucoma have been reported; One report has also described homozygous variants associated with Congenital thrombocytopenia, autosomal recessive

Refs: 9521281; 10932274; 12687498; 12554688; 15477569; 15304601; 23334996

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SBF2 variants in ClinVar

10 Conditions Cataloged

Charcot-Marie-Tooth disease type 4Total: 1382

Inborn genetic diseasesTotal: 359

not providedTotal: 314

not specifiedTotal: 171

Charcot-Marie-Tooth disease type 4B2Total: 162

SBF2-related disorderTotal: 109

Charcot-Marie-Tooth diseaseTotal: 108

Tip-toe gaitTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030962.4. 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			7 clinvar	395 clinvar	6 clinvar	408
missense	1 clinvar	4 clinvar	795 clinvar	16 clinvar	1 clinvar	817
nonsense	30 clinvar	7 clinvar	2 clinvar			39
start loss						0
frameshift	16 clinvar	10 clinvar	2 clinvar			28
splice donor/acceptor (+/-2bp)	7 clinvar	22 clinvar	8 clinvar			37
Total	54	43	814	411	7	1329

Highest pathogenic variant AF is 0.000016211497

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030962.4	RefSeq	NP_112224.1	40	MANE Select
ENST00000256190.13	Ensembl	ENSP00000256190.8	40	MANE Select
NM_001386339.1	RefSeq	NP_001373268.1	41	Standard
NM_001386342.1	RefSeq	NP_001373271.1	39	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Metabolism of lipids
Metabolism
Rab regulation of trafficking

Biological Process

myelination
regulation of GTPase activity
protein tetramerization

Molecular Function

protein binding
Rab guanyl-nucleotide exchange factor activity
phosphatase regulator activity
phosphatase binding
phosphatidylinositol binding

Cellular Component

vacuolar membrane
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000256190
Coding exons: 40
Length: 515541
Individuals with no LoFs: 125682
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 125748
p: 0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.19	849	952	0.891	0.0000507	12151
Missense (PolyPhen)		197	298.43	0.66013		3792
Synonymous	-0.870	362	342	1.06	0.0000179	3533
Loss of Function	5.98	35	99.3	0.353	0.00000523	1209

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00028	0.00028	rare
South Asian	0.00036	0.00036	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide exchange factor (GEF) which may activate RAB28. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. {ECO:0000269|PubMed:20937701}.;

Recessive Scores

pRec: 0.169

Intolerance Scores

LoFtool: 0.0995
RVIS EVS: -2
RVIS percentile EVS: 1.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.874

Gene Damage Prediction

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