MYOZ2
protein-codingmyozenin 2, the group of Myozenins
Gene summary
The protein encoded by this gene belongs to a family of sarcomeric proteins that bind to calcineurin, a phosphatase involved in calcium-dependent signal transduction in diverse cell types. These family members tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells, and thus they are important for calcineurin signaling. Mutations in this gene cause cardiomyopathy familial hypertrophic type 16, a hereditary heart disorder. [provided by RefSeq, Aug 2011]
- C4orf5
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~52.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013455
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005045
Submitter: ClinGen
MYOZ2 was first reported in relation to hypertrophic cardiomyopathy (HCM) in humans in 2007 (Osio et al., PMID: 17347475). MYOZ2 encodes a protein which belongs to a family of sarcomeric proteins that bind to calcineurin and are important in calcineurin signaling. The MYOZ2 gene has been related with HCM in 7 probands across 4 publications. One missense variant with experimental evidence to support its pathogenicity was identified in a patient and was shown to segregate with 5 additional family members (Osio et al., 2007, PMID: 17347475). Five additional unique variants with little to no experimental evidence to support their pathogenicity were reported (Osio et al., 2007, PMID: 17347475; Posch et al., 2008, PMID: 18591919; Cecconi M, et al., 2016, PMID: 27600940). Another unique missense variant was identified in a proband who also harbored a variant in MYH7 and was excluded as causative (Guo et al., 2017, PMID: 28296734). The mechanism for disease is unknown. The gene-disease relationship is supported by expression data in the heart (Frey N, et al., 2000, PMID: 11114196), a mouse model that exhibits features of hypertrophic cardiomyopathy including left ventricular hypertrophy and interstitial cardiac fibrosis (Ruggiero A, et al., 2013, PMID: 22987565), and protein interaction with ACTN2 (Frey N, et al., 2000, PMID: 11114196). In summary, the evidence to support the gene-disease association between MYOZ2 and HCM is disputed as there has been a lack of supportive evidence since the previous curation and the points were reduced due to the new SOP. More evidence is needed to either support or entirely refute the role MYOZ2 plays in this disease. This gene-disease pair was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on June 26th, 2017. It was reevaluated on October 27th, 2022. As a result of this reevaluation, the classification changed from limited to disputed.
Inheritance Pattern: AD
Disease ID:MONDO:0024573
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013455
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013455
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Surveillance and preventive measures related to cardiac manifestations, which have been reported as including arrhythmias, may allow early diagnosis and medical management as well as pacemaker placement, which may reduce morbidity and mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MYOZ2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016599.5. 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 | 58 | 3 | 61 | |||
| missense | 1 | 155 | 14 | 170 | ||
| nonsense | 7 | 7 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 5 | 5 | ||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 1 | 174 | 72 | 3 | 250 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057683.1 | 5 | MANE Select | |
| Ensembl | ENSP00000306997.6 | 5 | MANE Select | |
| RefSeq | NP_001427574.1 | 6 | Standard | |
| RefSeq | NP_001427575.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- negative regulation of transcription by RNA polymerase II
- skeletal muscle tissue development
- biological_process
- skeletal muscle fiber adaptation
- sarcomere organization
Molecular Function
- actin binding
- protein binding
- protein phosphatase 2B binding
- telethonin binding
- FATZ binding
Cellular Component
- actin cytoskeleton
- sarcomere
- Z disc
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000307128
- Coding exons
- 5
- Length
- 52006
- Individuals with no LoFs
- 125721
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125745
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.539 | 125 | 143 | 0.873 | 0.00000693 | 1746 |
| Missense (PolyPhen) | 44 | 53.059 | 0.82927 | 647 | ||
| Synonymous | -0.0712 | 49 | 48.4 | 1.01 | 0.00000225 | 498 |
| Loss of Function | 1.41 | 6 | 11.1 | 0.543 | 5.63e-7 | 138 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Myozenins may serve as intracellular binding proteins involved in linking Z line proteins such as alpha-actinin, gamma- filamin, TCAP/telethonin, LDB3/ZASP and localizing calcineurin signaling to the sarcomere. Plays an important role in the modulation of calcineurin signaling. May play a role in myofibrillogenesis.;
Recessive Scores
- pRec
- 0.158
Intolerance Scores
- LoFtool
- 0.568
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 33.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.323
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |