UNC45B

protein-coding

unc-45 myosin chaperone B, the group of Armadillo like helical domain containing

Gene summary

This gene encodes a co-chaperone required for folding and accumulation of type II myosins. The protein consists of three tetratricopeptide repeat motifs at the N-terminus that form a complex with heat shock protein 90, a central region of unknown function that is conserved in all Unc-45 proteins, and a C-terminal Unc-45/Cro1/She4 domain. The protein is expressed at high levels in striated muscle, where its muscle myosin chaperone activity is dependent on heat shock protein 90 acting as a co-chaperone. A missense mutation in this gene has been associated with cataract development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

Previous symbols:

CMYA4

MANE transcript

NM_001267052.2

Inheritance

AD, AR

ClinVar variants

P:6U:210B:64

Top phenotype

Myofibrillar myopathy 11

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr17:35,147,817-35,189,345

External References & Databases

Ensembl (ENSG00000141161)

Transcript & Mutation Effects

hg38 • Region Span ~41.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cataract 43STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014565

Submitter: G2P

cataract 43LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014565

Submitter: Labcorp Genetics (formerly Invitae)

early-onset posterior subcapsular cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018610

Submitter: Orphanet

early-onset nuclear cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020376

Submitter: Orphanet

myofibrillar myopathy 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030927

Submitter: PanelApp Australia

myofibrillar myopathy 11MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030927

Submitter: Ambry Genetics

myofibrillar myopathy 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030927

Submitter: Labcorp Genetics (formerly Invitae)

myofibrillar myopathy 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030927

Submitter: G2P

Clinical Genomic Database (CGD)

Myofibrillar myopathy 11AD

Manifestation: Cardiovascular; Musculoskeletal; Ophthalmologic

Intervention: Cardiovascular

Rationale: Among other findings, the condition can involve arrhthymias and cardiomyopathy, and awareness may allow surveillance and early management of these sequelae

Refs: 24549050; 31852522; 33217308

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UNC45B variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 177

not providedTotal: 159

UNC45B-related disorderTotal: 26

Myofibrillar myopathy 11Total: 13

Cataract 43Total: 7

Dilated cardiomyopathy 1ATotal: 3

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001267052.2. 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			2 clinvar	36 clinvar	9 clinvar	47
missense	3 clinvar	3 clinvar	205 clinvar	15 clinvar	4 clinvar	230
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	3	3	210	51	13	280

Highest pathogenic variant AF is 0.00012011186

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001267052.2	RefSeq	NP_001253981.1	19	MANE Select
ENST00000394570.7	Ensembl	ENSP00000378071.2	19	MANE Select
NM_001033576.2	RefSeq	NP_001028748.1	19	Standard
NM_001308281.1	RefSeq	NP_001295210.1	17	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
unc45b	Danio rerio	Structure: lens fiber cell Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

unc45b

Danio rerio

Structure: lens fiber cell

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

lens development in camera-type eye
muscle organ development
cell differentiation
chaperone-mediated protein folding

Molecular Function

protein binding
Hsp90 protein binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000268876
Coding exons: 19
Length: 41529
Individuals with no LoFs: 125667
Homozygous LoFs: 0
Heterozygous LoFs: 81
Defined: 125748
p: 0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.404	569	543	1.05	0.0000320	6048
Missense (PolyPhen)		156	154.62	1.0089		1654
Synonymous	0.607	213	225	0.948	0.0000133	1887
Loss of Function	2.04	30	44.8	0.670	0.00000257	496

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.00046	0.00046	rare
European (Non-Finnish)	0.00035	0.00034	rare
South Asian	0.00053	0.00052	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a co-chaperone for HSP90 and is required for proper folding of the myosin motor domain. Plays a role in sarcomere formation during muscle cell development. Is necessary for normal early lens development. {ECO:0000250|UniProtKB:Q6DGE9, ECO:0000250|UniProtKB:Q8CGY6}.;
Disease: DISEASE: Cataract 43 (CTRCT43) [MIM:616279]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. {ECO:0000269|PubMed:24549050}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.840
RVIS EVS: 0.3
RVIS percentile EVS: 71.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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