CRYAA
protein-codingcrystallin alpha A, the group of Small heat shock proteins
Gene summary
Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. Post-translational modifications decrease the ability to chaperone. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Defects in this gene cause autosomal dominant congenital cataract (ADCC). [provided by RefSeq, Jan 2014]
- CRYA1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020373
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018611
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0021548
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011413
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011413
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011413
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011413
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0020376
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015300
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CRYAA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000394.4. 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 | 1 | 19 | 6 | 26 | ||
| missense | 4 | 8 | 47 | 1 | 60 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 4 | 10 | 49 | 20 | 6 | 89 |
Highest pathogenic variant AF is 0.0000052104174
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000385.1 | 3 | MANE Select | |
| Ensembl | ENSP00000291554.2 | 3 | MANE Select | |
| RefSeq | NP_001350695.1 | 3 | Standard | |
| Ensembl | ENSP00000381200.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cryaa | Danio rerio | Structure: eye Quality: opaque abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein processing in endoplasmic reticulum - Homo sapiens (human)
Biological Process
- visual perception
- negative regulation of intracellular transport
- protein refolding
- negative regulation of apoptotic process
- protein stabilization
Molecular Function
- structural constituent of eye lens
- protein binding
- identical protein binding
- metal ion binding
- unfolded protein binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000291554
- Coding exons
- 3
- Length
- 3798
- Individuals with no LoFs
- 125470
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125472
- p
- 0.00000797
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.348 | 107 | 118 | 0.910 | 0.00000956 | 1118 |
| Missense (PolyPhen) | 31 | 38.871 | 0.79752 | 348 | ||
| Synonymous | -0.649 | 60 | 53.9 | 1.11 | 0.00000465 | 358 |
| Loss of Function | 1.61 | 2 | 6.38 | 0.314 | 3.44e-7 | 64 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Contributes to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions. {ECO:0000269|PubMed:22120592}.;
- Disease
- DISEASE: Note=Alpha-crystallin A 1-172 is found at nearly twofold higher levels in diabetic lenses than in age-matched control lenses. {ECO:0000269|PubMed:12356833}.; DISEASE: Cataract 9, multiple types (CTRCT9) [MIM:604219]: 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. CTRCT9 includes nuclear, zonular central nuclear, anterior polar, cortical, embryonal, anterior subcapsular, fan-shaped, and total cataracts, among others. In some cases cataract is associated with microcornea without any other systemic anomaly or dysmorphism. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. {ECO:0000269|PubMed:11123904, ECO:0000269|PubMed:14512969, ECO:0000269|PubMed:16453125, ECO:0000269|PubMed:18302245, ECO:0000269|PubMed:18407550, ECO:0000269|PubMed:23508780, ECO:0000269|PubMed:9467006}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.260
Intolerance Scores
- LoFtool
- 0.255
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.69
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.641
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |