OSBPL2

protein-coding

oxysterol binding protein like 2, the group of Oxysterol binding proteins

Gene summary

This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain, although the encoded protein contains only the sterol-binding domain. In vitro studies have shown that the encoded protein can bind strongly to phosphatic acid and weakly to phosphatidylinositol 3-phosphate, but cannot bind to 25-hydroxycholesterol. The protein associates with the Golgi apparatus. Transcript variants encoding different isoforms have been described. [provided by RefSeq, Sep 2014]

MANE transcript

NM_144498.4

Inheritance

ClinVar variants

P:6U:106B:61

Top phenotype

Deafness, autosomal dominant 67

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr20:62,231,922-62,296,213

External References & Databases

Ensembl (ENSG00000130703)

Transcript & Mutation Effects

hg38 • Region Span ~64.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

OSBPL2 was reported with autosomal dominant nonsyndromic hearing loss in 2015 (Xing et al., PMID: 25077649). At least 4 unique variants (missense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 4 probands in 3 publications (PMID: 25077649, 25759012, 30894143). Variants in this gene segregated with disease in 31 additional family members. This gene-disease association is supported by animal models and expression studies. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 2/6/2020.

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 67STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014594

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 67STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014594

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing loss 67MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014594

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 67AD

Manifestation: Audiologic/Otolaryngologic

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

Refs: 25077649; 25759012

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OSBPL2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 214

Inborn genetic diseasesTotal: 48

not specifiedTotal: 23

OSBPL2-related disorderTotal: 14

Autosomal dominant nonsyndromic hearing loss 67Total: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144498.4. 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			5 clinvar	48 clinvar	3 clinvar	56
missense			92 clinvar	8 clinvar	2 clinvar	102
nonsense			2 clinvar			2
start loss						0
frameshift	5 clinvar	1 clinvar	2 clinvar			8
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	5	1	106	56	5	173

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_144498.4	RefSeq	NP_653081.1	13	MANE Select
ENST00000313733.9	Ensembl	ENSP00000316649.3	13	MANE Select
NM_001278649.3	RefSeq	NP_001265578.1	9	Standard
NM_001363878.2	RefSeq	NP_001350807.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of lipids
Metabolism
Synthesis of bile acids and bile salts
Bile acid and bile salt metabolism
Metabolism of steroids

Biological Process

bile acid biosynthetic process
sterol transport

Molecular Function

protein binding
lipid binding
sterol transporter activity
cholesterol binding
sterol binding

Cellular Component

cytosol
membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000313733
Coding exons: 13
Length: 57689
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.97	197	292	0.675	0.0000171	3194
Missense (PolyPhen)		56	142.43	0.39318		1473
Synonymous	0.608	112	120	0.930	0.00000857	858
Loss of Function	3.61	7	27.4	0.256	0.00000125	320

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000062	0.000058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000070	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds phospholipids; exhibits strong binding to phosphatidic acid and weak binding to phosphatidylinositol 3- phosphate (PubMed:11279184). Binds 25-hydroxycholesterol (PubMed:17428193). {ECO:0000269|PubMed:11279184, ECO:0000269|PubMed:17428193}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.608
RVIS EVS: -0.6
RVIS percentile EVS: 18.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.757

Gene Damage Prediction

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