CRYAB

Chr 11

crystallin alpha B

Also known as: CMD1II, CRYA2, CTPP2, CTRCT16, HEL-S-101, HSPB5, MFM2, MFM2A

NCBI Gene: 1410 ENSG00000109846 UniProt: P02511

Alpha-B crystallin functions as a molecular chaperone that prevents protein aggregation under stress conditions and contributes to lens transparency. Mutations cause autosomal dominant or recessive disorders including dilated cardiomyopathy, cataracts, and myofibrillar myopathies with either adult or infantile onset depending on the specific variant. The gene is not highly constrained against loss-of-function variation, reflecting its tolerance to certain types of genetic variants.

ResearchSummary from RefSeq, OMIM, UniProt

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. 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. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2019]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.43

Clinical Summary— CRYAB

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.43LOEUF

pLI 0.022

Z-score 0.93

OE 0.57 (0.26–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.48Z-score

OE missense 0.87 (0.73–1.03)

88 obs / 101.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.26–1.43)

0≤0.351.4

Missense OE?0.87 (0.73–1.03)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 3 / 5.3Missense obs/exp: 88 / 101.5Syn Z: 0.72

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateCRYAB-related infantile hypertonic myofibrillar myopathyLOFAR

definitiveCRYAB-related crystallinopathy with cataract, skeletal myopathy and/or cardiomyopathyDNAD

limitedCRYAB-related cataract, multiple typesOTHERAR

This gene — mechanism propensity

0.83top 10%

GOF

0.5955th %ile

LOF

0.3453th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe conclude that (1) despite its reduced expression, the mutant protein exerts a dominant negative effect; (2) mutations in alphaB-crystallin are an infrequent cause of myofibrillar myopathy; (3) alphaB-crystallin-related myopathies display phenotypic heterogeneity.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References