CRYGS

protein-coding

crystallin gamma S, 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. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. This gene encodes a protein initially considered to be a beta-crystallin but the encoded protein is monomeric and has greater sequence similarity to other gamma-crystallins. This gene encodes the most significant gamma-crystallin in adult eye lens tissue. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. [provided by RefSeq, Jul 2008]

Previous symbols:

CRYG8

MANE transcript

NM_017541.4

Inheritance

ClinVar variants

P:7U:47B:8

Top phenotype

Cataract 20, multiple types

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr3:186,538,441-186,546,702

External References & Databases

Ensembl (ENSG00000213139)

Transcript & Mutation Effects

hg38 • Region Span ~8.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cataract 20 multiple typesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007284

Submitter: G2P

cataract 20 multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007284

Submitter: Ambry Genetics

early-onset sutural cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020372

Submitter: Orphanet

early-onset lamellar cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018611

Submitter: Orphanet

cataract 20 multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007284

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Cataract 20, multiple typesAD

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: 16141006; 18587492; 19262743

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRYGS variants in ClinVar

8 Conditions Cataloged

Cataract 20 multiple typesTotal: 36

Inborn genetic diseasesTotal: 22

not providedTotal: 14

CRYGS-related disorderTotal: 7

not specifiedTotal: 2

Developmental cataractTotal: 1

See casesTotal: 1

Retinitis pigmentosaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017541.4. 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				2 clinvar	2 clinvar	4
missense	4 clinvar	3 clinvar	44 clinvar	4 clinvar		55
nonsense			2 clinvar			2
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	4	3	47	6	2	62

Highest pathogenic variant AF is 6.8417233e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017541.4	RefSeq	NP_060011.1	3	MANE Select
ENST00000307944.6	Ensembl	ENSP00000312099.5	3	MANE Select
ENST00000392499.6	Ensembl	ENSP00000376287.2	3	Standard
ENST00000392499.7	Ensembl	ENSP00000376287.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

morphogenesis of an epithelium
lens development in camera-type eye

Molecular Function

structural constituent of eye lens
protein binding

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392499
Coding exons: 3
Length: 8262
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125747
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.243	102	109	0.935	0.00000657	1181
Missense (PolyPhen)		23	33.592	0.68468		423
Synonymous	1.11	27	35.4	0.763	0.00000188	313
Loss of Function	1.62	4	9.33	0.429	4.83e-7	104

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Crystallins are the dominant structural components of the vertebrate eye lens.;
Disease: DISEASE: Cataract 20, multiple types (CTRCT20) [MIM:116100]: 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. CTRCT20 includes progressive polymorphic anterior, posterior, or peripheral cortical. {ECO:0000269|PubMed:16141006}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.560
RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.192

Gene Damage Prediction

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