CST3

cystatin C, the group of Cystatins, type 2

Basic information

Region (hg38): 20:23626705-23638473

Links

ENSG00000101439 ∙ NCBI:1471 ∙ OMIM:604312 ∙ HGNC:2475 ∙ Uniprot:P01034 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ACys amyloidosis (Supportive), mode of inheritance: AD
• ACys amyloidosis (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebral amyloid angiopathy, CST3 related	AD	General	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	Cardiovascular; Neurologic	4655034; 3495457; 2900981; 11760381; 16612982; 18566660

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CST3 gene.

• not provided (20 variants)
• Inborn genetic diseases (7 variants)
• not specified (5 variants)
• CST3-related Leukodystrophy (3 variants)
• Hereditary cerebral amyloid angiopathy, Icelandic type (2 variants)
• Age related macular degeneration 11 (1 variants)
• Hereditary cerebral amyloid angiopathy, Icelandic type;Age related macular degeneration 11 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CST3 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				3	5	8
missense			9		5	14
nonsense			2			2
start loss						0
frameshift			2			2
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region						0
non coding				2	2	4
Total	0	0	14	5	12

Variants in CST3

This is a list of pathogenic ClinVar variants found in the CST3 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-23633933-T-C			Benign (Dec 21, 2023)
20-23633940-C-T		not specified	Benign/Likely benign (Jan 25, 2024)
20-23633981-G-A			Uncertain significance (Oct 01, 2023)
20-23633995-G-A		not specified	Uncertain significance (Jun 29, 2023)
20-23633996-C-G			Uncertain significance (Jul 29, 2022)
20-23633996-CT-C		CST3-related Leukodystrophy	Uncertain significance (Sep 01, 2023)
20-23635252-AC-A		CST3-related Leukodystrophy	Uncertain significance (Sep 01, 2023)
20-23635268-GC-G			Uncertain significance (Jul 01, 2023)
20-23635271-G-A		CST3-related Leukodystrophy • Hereditary cerebral amyloid angiopathy, Icelandic type	Uncertain significance (Nov 20, 2023)
20-23635276-T-C			Uncertain significance (Jan 26, 2024)
20-23635321-G-A		not specified	Uncertain significance (Aug 17, 2021)
20-23635324-C-T		not specified	Uncertain significance (Oct 20, 2021)
20-23635329-C-T			Likely benign (Nov 27, 2023)
20-23635330-A-T		Hereditary cerebral amyloid angiopathy, Icelandic type	Pathogenic (Feb 15, 1994)
20-23635344-G-C			Uncertain significance (Nov 24, 2023)
20-23637603-C-A			Likely benign (Mar 08, 2022)
20-23637609-G-A			Likely benign (Sep 05, 2021)
20-23637628-G-T			Benign (Apr 17, 2023)
20-23637640-C-T		not specified	Uncertain significance (Nov 15, 2021)
20-23637649-C-A		not specified	Benign (Oct 03, 2022)
20-23637651-C-T		Hereditary cerebral amyloid angiopathy, Icelandic type	Uncertain significance (Mar 05, 2021)
20-23637664-TGTC-T		Hereditary cerebral amyloid angiopathy, Icelandic type	Uncertain significance (Apr 04, 2024)
20-23637678-T-C		not specified	Uncertain significance (Jan 26, 2022)
20-23637679-T-G		not specified	Uncertain significance (Mar 27, 2023)
20-23637695-G-A			Likely benign (Aug 28, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CST3	protein_coding	protein_coding	ENST00000398411	3	10577

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00390	0.661	125726	0	21	125747	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.497	81	69.4	1.17	0.00000365	898
Missense in Polyphen		30	26.62	1.127		300
Synonymous	-0.518	33	29.4	1.12	0.00000180	291
Loss of Function	0.581	4	5.47	0.732	3.19e-7	61

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000185	0.000185
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000132	0.000132
Middle Eastern	0.000109	0.000109
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.
• Disease: DISEASE: Amyloidosis 6 (AMYL6) [MIM:105150]: A hereditary generalized amyloidosis due to cystatin C amyloid deposition. Cystatin C amyloid accumulates in the walls of arteries, arterioles, and sometimes capillaries and veins of the brain, and in various organs including lymphoid tissue, spleen, salivary glands, and seminal vesicles. Amyloid deposition in the cerebral vessels results in cerebral amyloid angiopathy, cerebral hemorrhage and premature stroke. Cystatin C levels in the cerebrospinal fluid are abnormally low. {ECO:0000269|PubMed:1352269, ECO:0000269|PubMed:2541223}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 11 (ARMD11) [MIM:611953]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:11815350, ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:2764935}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Salivary secretion - Homo sapiens (human);Neutrophil degranulation;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (Consensus)

Recessive Scores

• pRec: 0.625

Intolerance Scores

• loftool: 0.691
• rvis_EVS: 0.13
• rvis_percentile_EVS: 62.74

Haploinsufficiency Scores

• pHI: 0.162
• hipred: N
• hipred_score: 0.261
• ghis: 0.406

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.874

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cst3
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); neoplasm; muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: defense response;negative regulation of peptidase activity;negative regulation of collagen catabolic process;negative regulation of extracellular matrix disassembly;negative regulation of endopeptidase activity;regulation of tissue remodeling;neutrophil degranulation;post-translational protein modification;cellular protein metabolic process;negative regulation of proteolysis;negative regulation of elastin catabolic process;negative regulation of blood vessel remodeling;supramolecular fiber organization
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;extracellular exosome;tertiary granule lumen;ficolin-1-rich granule lumen
• Molecular function: amyloid-beta binding;protease binding;endopeptidase inhibitor activity;cysteine-type endopeptidase inhibitor activity;protein binding;identical protein binding