CRYBA4

protein-coding

crystallin beta A4, the group of Beta-gamma crystallins

Gene summary

Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta acidic group member, is part of a gene cluster with beta-B1, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001886.3

Inheritance

AD, AR

ClinVar variants

P:6U:46B:30

Top phenotype

Cataract 23

gnomAD constraint

pLI —, LoF o/e 0.89

Max pathogenic AF

—

Genomic locus

chr22:26,621,963-26,630,669

External References & Databases

Ensembl (ENSG00000196431)

Transcript & Mutation Effects

hg38 • Region Span ~8.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cataract 23STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012489

Submitter: Labcorp Genetics (formerly Invitae)

cataract 23MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012489

Submitter: Ambry Genetics

early-onset lamellar cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018611

Submitter: Orphanet

cataract - microcornea syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015300

Submitter: Orphanet

cataract 23DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012489

Submitter: G2P

cataract 23LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012489

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cataract 23AD

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

Refs: 16960806; 20577656

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRYBA4 variants in ClinVar

8 Conditions Cataloged

Cataract 23Total: 62

not providedTotal: 24

Inborn genetic diseasesTotal: 16

CRYBA4-related disorderTotal: 8

not specifiedTotal: 5

Early-onset non-syndromic cataractTotal: 1

CRYBA4-related disordersTotal: 1

Developmental cataractTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001886.3. 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				20 clinvar	1 clinvar	21
missense	3 clinvar	2 clinvar	42 clinvar	7 clinvar		54
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			3 clinvar	2 clinvar		5
Total	3	3	46	29	1	82

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001886.3	RefSeq	NP_001877.1	5	MANE Select
ENST00000354760.4	Ensembl	ENSP00000346805.3	5	MANE Select
ENST00001133929.1	Ensembl	ENSP00000808296.1	5	Standard
XM_006724140.4	RefSeq	XP_006724203.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cellular response to heat stress
HSF1 activation
Attenuation phase
HSF1-dependent transactivation
Regulation of HSF1-mediated heat shock response

Biological Process

visual perception
camera-type eye development

Molecular Function

molecular_function
structural constituent of eye lens
protein binding

Cellular Component

cellular_component

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354760
Coding exons: 5
Length: 8709
Individuals with no LoFs: 124688
Homozygous LoFs: 5
Heterozygous LoFs: 1055
Defined: 125748
p: 0.00422

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.694	105	127	0.827	0.00000854	1271
Missense (PolyPhen)		31	51.076	0.60694		528
Synonymous	-0.287	56	53.3	1.05	0.00000398	368
Loss of Function	0.411	14	15.8	0.888	0.00000114	122

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0011	notable
Latino/Admixed American	0.0022	0.0022	notable
Ashkenazi Jewish	0.0011	0.0011	notable
East Asian	0.00071	0.00071	rare
Finnish	0.0076	0.0075	notable
European (Non-Finnish)	0.0060	0.0060	notable
South Asian	0.0025	0.0026	notable
Other	0.0041	0.0041	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Crystallins are the dominant structural components of the vertebrate eye lens.;
Disease: DISEASE: Cataract 23, multiple types (CTRCT23) [MIM:610425]: 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. CTRCT23 is a zonular cataract. Zonular or lamellar cataracts are opacities, broad or narrow, usually consisting of powdery white dots affecting only certain layers or zones between the cortex and nucleus of an otherwise clear lens. The opacity may be so dense as to render the entire central region of the lens completely opaque, or so translucent that vision is hardly if at all impeded. Zonular cataracts generally do not involve the embryonic nucleus, though sometimes they involve the fetal nucleus. Usually sharply separated from a clear cortex outside them, they may have projections from their outer edges known as riders or spokes. {ECO:0000269|PubMed:16960806, ECO:0000269|PubMed:20577656}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.133

Intolerance Scores

LoFtool: 0.740
RVIS EVS: 0.22
RVIS percentile EVS: 68.13

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.299

Gene Damage Prediction

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