CRYAB

crystallin alpha B, the group of Small heat shock proteins

Basic information

Region (hg38): 11:111908564-111923722

Previous symbols: [ "CRYA2" ]

Links

ENSG00000109846 ∙ NCBI:1410 ∙ OMIM:123590 ∙ HGNC:2389 ∙ Uniprot:P02511 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cataract 16 multiple types (Limited), mode of inheritance: AD
• fatal infantile hypertonic myofibrillar myopathy (Limited), mode of inheritance: AR
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• early-onset nuclear cataract (Supportive), mode of inheritance: AD
• early-onset posterior polar cataract (Supportive), mode of inheritance: AD
• fatal infantile hypertonic myofibrillar myopathy (Supportive), mode of inheritance: AR
• myofibrillar myopathy 2 (Supportive), mode of inheritance: AD
• early-onset lamellar cataract (Supportive), mode of inheritance: AD
• fatal infantile hypertonic myofibrillar myopathy (Limited), mode of inheritance: AR
• myofibrillar myopathy 2 (Strong), mode of inheritance: AD
• cataract 16 multiple types (Strong), mode of inheritance: AR
• myofibrillar myopathy 2 (Strong), mode of inheritance: AD
• fatal infantile hypertonic myofibrillar myopathy (Strong), mode of inheritance: AR
• cataract 16 multiple types (Strong), mode of inheritance: AD
• dilated cardiomyopathy 1II (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myopathy, myofibrillar, 2; Cardiomyopathy, dilated, 1II	AD	Cardiovascular	Individuals with Myopathy, myofibrillar, 2 typically present with slowly progressive weakness, and a significant proportion of individuals demonstrate cardiomyopathy, such that surveillance for arrhythmia or conduction defects may allow early treatment (eg, pacemaker, ICD); Cardiac transplantation may be necessary in individuals with severe forms of cardiomyopathy; Individuals with Cardiomyopathy, dilated, 1II may present with arrhythmias, including sequelae such as sudden cardiac death, and surveillance (eg, with electrocardiogram and echocardiogram) may allow early management as described for other CRYAB-related cardiac manifestations	Cardiovascular; Musculoskeletal; Ophthalmologic	570292; 8000975; 9731540; 11577372; 14681890; 16483541; 16793013; 20301672; 21337604; 21920752; 23197161; 23590293
Individuals have been described with a combination of cardiovascular, musculoskeletal, and ophthalmologic manifestations, as well as apparently isolated findings affecting each of these organ systems

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CRYAB gene.

• Dilated cardiomyopathy 1II (2 variants)
• Myofibrillar myopathy 2 (1 variants)
• Developmental cataract (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CRYAB gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	55	2	58
missense		1	122	1		124
nonsense	1		1			2
start loss						0
frameshift	3	2	6			11
inframe indel			3			3
splice donor/acceptor (+/-2bp)			1			1
splice region			11	2	1	14
non coding			8	20	5	33
Total	4	3	142	76	7

Variants in CRYAB

This is a list of pathogenic ClinVar variants found in the CRYAB region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-111908657-T-C		Fatal infantile hypertonic myofibrillar myopathy • Myofibrillar Myopathy, Dominant • Cataract 16 multiple types	Uncertain significance (Jan 12, 2018)
11-111908704-C-T		Fatal infantile hypertonic myofibrillar myopathy • Myofibrillar myopathy 2 • Cataract 16 multiple types	Uncertain significance (Jan 13, 2018)
11-111908725-A-G		Myofibrillar myopathy 2 • Posterior polar cataract • Myofibrillar Myopathy, Dominant	Uncertain significance (Jun 14, 2016)
11-111908726-C-G		Myofibrillar myopathy 2 • Cataract 16 multiple types • Fatal infantile hypertonic myofibrillar myopathy	Conflicting classifications of pathogenicity (Jan 13, 2018)
11-111908748-A-G		not specified	Likely benign (Nov 08, 2016)
11-111908761-C-G			Likely benign (May 12, 2021)
11-111908766-AT-A		Cataract 16 multiple types	Likely pathogenic (-)
11-111908768-T-A		Dilated cardiomyopathy 1II	Uncertain significance (Aug 31, 2021)
11-111908770-C-A		Dilated cardiomyopathy 1II	Uncertain significance (Nov 01, 2022)
11-111908772-TG-T		Myofibrillar myopathy 2 • CRYAB-related disorder	Conflicting classifications of pathogenicity (Apr 19, 2024)
11-111908773-G-A		Dilated cardiomyopathy 1II	Likely benign (Mar 13, 2022)
11-111908776-G-T		Dilated cardiomyopathy 1II • Cardiovascular phenotype • not specified	Likely benign (Jan 20, 2024)
11-111908777-GC-G		Myofibrillar myopathy 2	Pathogenic (Dec 17, 2019)
11-111908781-C-A		Dilated cardiomyopathy 1II	Uncertain significance (Dec 23, 2021)
11-111908781-C-T		Cardiomyopathy • Dilated cardiomyopathy 1II • Cardiovascular phenotype	Uncertain significance (Feb 01, 2023)
11-111908782-G-A		not specified • Dilated cardiomyopathy 1II • Cardiovascular phenotype	Likely benign (Aug 17, 2023)
11-111908782-G-T		Dilated cardiomyopathy 1II • Cardiovascular phenotype • not specified	Likely benign (Feb 19, 2024)
11-111908783-G-A		Cardiovascular phenotype	Uncertain significance (Jun 16, 2020)
11-111908783-G-T			Uncertain significance (May 04, 2020)
11-111908786-ACAGCAGG-A		Dilated cardiomyopathy 1II	Uncertain significance (Aug 07, 2022)
11-111908788-A-G		Dilated cardiomyopathy 1II • Cardiovascular phenotype	Likely benign (Jul 19, 2022)
11-111908789-G-C		Dilated cardiomyopathy 1II • Myofibrillar myopathy 2	Uncertain significance (Oct 25, 2021)
11-111908793-G-C		Dilated cardiomyopathy 1II	Uncertain significance (Feb 19, 2021)
11-111908794-C-T		Dilated cardiomyopathy 1II	Likely benign (Dec 07, 2022)
11-111908796-T-A		Dilated cardiomyopathy 1II	Uncertain significance (Mar 21, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CRYAB	protein_coding	protein_coding	ENST00000533475	3	15158

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0225	0.778	125736	0	12	125748	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.476	88	102	0.867	0.00000637	1135
Missense in Polyphen		35	49.896	0.70146		521
Synonymous	0.723	33	38.7	0.852	0.00000212	358
Loss of Function	0.926	3	5.30	0.566	2.30e-7	67

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000119	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000622	0.0000615
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May contribute 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.
• Disease: DISEASE: Myopathy, myofibrillar, 2 (MFM2) [MIM:608810]: A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM2 is characterized by weakness of the proximal and distal limb muscles, weakness of the neck, velopharynx and trunk muscles, hypertrophic cardiomyopathy, and cataract in a subset of patients. {ECO:0000269|PubMed:12601044, ECO:0000269|PubMed:14681890, ECO:0000269|PubMed:21920752, ECO:0000269|PubMed:9731540}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cataract 16, multiple types (CTRCT16) [MIM:613763]: 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. CTRCT16 includes posterior polar cataract, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. {ECO:0000269|PubMed:11577372}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=CRYAB mutations may be involved in restrictive cardiomyopathy (RCM), a rare non-ischemic myocardial disease. RCM is characterized by restrictive ventricular-filling physiology in the presence of normal or reduced diastolic and/or systolic volumes (of 1 or both ventricles), biatrial enlargement, and normal ventricular wall thickness. {ECO:0000269|PubMed:28493373}.; DISEASE: Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related (MFMFIH-CRYAB) [MIM:613869]: A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFMFIH-CRYAB has onset in the first weeks of life after a normal neonatal period. Affected infants show rapidly progressive muscular rigidity of the trunk and limbs associated with increasing respiratory difficulty resulting in death before age 3 years. {ECO:0000269|PubMed:21337604}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1II (CMD1II) [MIM:615184]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:16483541, ECO:0000269|PubMed:16793013}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Longevity regulating pathway - multiple species - Homo sapiens (human);Protein processing in endoplasmic reticulum - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.565

Intolerance Scores

• loftool: 0.344
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.42

Haploinsufficiency Scores

• pHI: 0.513
• hipred: Y
• hipred_score: 0.767
• ghis: 0.470

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.951

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cryab
• Phenotype: muscle phenotype; cellular phenotype; vision/eye phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: cryaba
• Affected structure: muscle cell
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: response to hypoxia;lens development in camera-type eye;protein folding;muscle contraction;tubulin complex assembly;muscle organ development;multicellular organism aging;negative regulation of gene expression;regulation of cell death;negative regulation of cell growth;microtubule polymerization or depolymerization;response to estradiol;negative regulation of intracellular transport;negative regulation of protein homooligomerization;response to hydrogen peroxide;negative regulation of apoptotic process;negative regulation of cysteine-type endopeptidase activity involved in apoptotic process;protein stabilization;protein homooligomerization;stress-activated MAPK cascade;apoptotic process involved in morphogenesis;cellular response to gamma radiation;regulation of cellular response to heat;negative regulation of amyloid fibril formation;negative regulation of reactive oxygen species metabolic process
• Cellular component: nucleus;nucleoplasm;cytoplasm;mitochondrion;Golgi apparatus;cytosol;cell surface;postsynaptic density;microtubule cytoskeleton;Z disc;axon;M band;actin filament bundle;dendritic spine;perikaryon;myelin sheath;extracellular exosome;synaptic membrane;cardiac myofibril
• Molecular function: amyloid-beta binding;structural constituent of eye lens;protein binding;microtubule binding;identical protein binding;protein homodimerization activity;protein-containing complex binding;metal ion binding;unfolded protein binding