CRYM
protein-codingcrystallin mu
Gene summary
Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles. Mutations in this gene have been associated with autosomal dominant non-syndromic deafness. [provided by RefSeq, Sep 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~64.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019497
Submitter: ClinGen
CRYM was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2003 (Abe et al., PMID: 12471561). Three variants (stop loss, missense) that have been reported in three probands in two publications are included in this curation. These variants segregated with disease in 7 additional family members in two families (PMIDs: 12471561, 32742378). The mechanism of pathogenicity is unknown. This gene-disease association is also supported by expression studies and in vitro functional assays (PMIDs: 16740909, 18448257, 24676347, 26915689). Of note, both homozygous and heterozygous CRYM null mice do not have hearing loss (PMID: 17264173). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 2/16/2017. It was reevaluated on 9/21/2021 (SOP v8). As a result of this reevaluation, the classification did not change. Although new literature was published (PMID: 32742378), the scoring still corresponded to a limited gene-disease relationship.
Inheritance Pattern: Unknown
Disease ID:MONDO:0014603
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic
Intervention: Audiologic/Otolaryngologic
Rationale: As some patients have been described with prelingual hearing loss, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CRYM variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001376256.1. 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 | 23 | 1 | 24 | |||
| missense | 58 | 13 | 71 | |||
| nonsense | 3 | 1 | 4 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 63 | 37 | 1 | 101 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001363185.1 | 8 | MANE Select | |
| Ensembl | ENSP00000461904.2 | 8 | MANE Select | |
| RefSeq | NP_001879.1 | 8 | Standard | |
| Ensembl | ENSP00000219599.3 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lysine catabolism
- Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism
- Metabolism of amino acids and derivatives
- Metabolism
- lysine degradation II (pipecolate pathway)
Biological Process
- negative regulation of transcription by RNA polymerase II
- lysine catabolic process
- sensory perception of sound
- thyroid hormone metabolic process
- oxidation-reduction process
Molecular Function
- transcription corepressor activity
- protein binding
- oxidoreductase activity, acting on the CH-NH2 group of donors, NAD or NADP as acceptor
- hormone binding
- protein homodimerization activity
Cellular Component
- nucleus
- cytoplasm
- mitochondrion
- peroxisomal matrix
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000219599
- Coding exons
- 8
- Length
- 64210
- Individuals with no LoFs
- 125618
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 129
- Defined
- 125748
- p
- 0.000517
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.984 | 138 | 175 | 0.790 | 0.00000889 | 2002 |
| Missense (PolyPhen) | 37 | 56.374 | 0.65633 | 690 | ||
| Synonymous | 0.894 | 61 | 70.6 | 0.865 | 0.00000370 | 652 |
| Loss of Function | 2.21 | 5 | 13.9 | 0.360 | 5.97e-7 | 171 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0058 | 0.0057 | notable |
| Latino/Admixed American | 0.00046 | 0.00046 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00037 | 0.00037 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Specifically catalyzes the reduction of imine bonds in brain substrates that may include cystathionine ketimine (CysK) and lanthionine ketimine (LK). Binds thyroid hormone which is a strong reversible inhibitor. Presumably involved in the regulation of the free intracellular concentration of triiodothyronine and access to its nuclear receptors. {ECO:0000269|PubMed:21332720}.;
Recessive Scores
- pRec
- 0.233
Intolerance Scores
- LoFtool
- 0.385
- RVIS EVS
- 0.06
- RVIS percentile EVS
- 58.53
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.278
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |