CBS
cystathionine beta-synthase
Basic information
Region (hg38): 21:43053190-43076943
Links
Phenotypes
GenCC
Source:
- classic homocystinuria (Definitive), mode of inheritance: AR
- classic homocystinuria (Definitive), mode of inheritance: AR
- classic homocystinuria (Strong), mode of inheritance: AR
- classic homocystinuria (Strong), mode of inheritance: AR
- classic homocystinuria (Strong), mode of inheritance: AR
- classic homocystinuria (Supportive), mode of inheritance: AR
- classic homocystinuria (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Homocystinuria due to cystathionine beta-synthase deficiency | AR | Biochemical; Hematologic; Ophthalmologic; Pharmacogenomic | Some individuals may respond to medical therapy (eg, pyridoxine, folic acid, betaine, hydroxycobalamin) and/or dietary therapy (eg, methionine restriction); Surveillance for and prompt treatment of thromboembolic complications can be beneficial; Awareness of ocular complications (eg, ectopia lentis) can allow prompt and appropriate treatment; Certain agents (eg, oral contraceptives) should be avoided, and special considerations may need to be taken into account if surgery is required | Biochemical; Cardiovascular; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic | 14018926; 13960563; 5658872; 5658866; 7325153; 6711564; 4033699; 934499; 3591841; 2116556; 7506602; 7967489; 7762555; 8554066; 8592550; 8940271; 9427154; 9787359; 10364517; 10338090; 10564686; 10780316; 11343305; 11596648; 12124992; 12227460; 12007221; 12118525; 11857551; 12552044; 14635102; 16205833; 17686644; 20142522; 20301697; 18280597; 19370759; 19819175; 21520339; 21308989; 21240075; 20567906; 21626167; 24168815; 24169224 |
ClinVar
This is a list of variants' phenotypes submitted to
- HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (805 variants)
- Classic homocystinuria (357 variants)
- not provided (287 variants)
- Familial thoracic aortic aneurysm and aortic dissection (221 variants)
- not specified (112 variants)
- Homocystinuria (61 variants)
- Connective tissue disorder (12 variants)
- Homocystinuria, pyridoxine-responsive (11 variants)
- Inborn genetic diseases (8 variants)
- Cardiovascular phenotype (8 variants)
- CBS-related condition (7 variants)
- Intellectual disability (4 variants)
- Homocystinuria, pyridoxine-nonresponsive (3 variants)
- See cases (3 variants)
- CYSTATHIONINE BETA-SYNTHETASE POLYMORPHISM (1 variants)
- Abnormality of metabolism/homeostasis (1 variants)
- Hyperhomocysteinemia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CBS 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 | 253 | 258 | ||||
| missense | 24 | 54 | 226 | 308 | ||
| nonsense | 13 | 17 | 13 | 46 | ||
| start loss | 1 | |||||
| frameshift | 22 | 32 | 55 | |||
| inframe indel | 7 | |||||
| splice donor/acceptor (+/-2bp) | 33 | 44 | ||||
| splice region ? | 2 | 20 | 54 | 76 | ||
| non coding ? | 26 | 135 | 52 | 213 | ||
| Total | 69 | 136 | 264 | 394 | 69 |
Highest pathogenic variant AF is 0.0000346
Variants in CBS
This is a list of pathogenic ClinVar variants found in the CBS region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 21-43053199-T-C | Classic homocystinuria | Benign/Likely benign (May 25, 2021) | ||
| 21-43053288-A-T | Classic homocystinuria | Uncertain significance (Jan 13, 2018) | ||
| 21-43053314-C-T | Classic homocystinuria | Benign/Likely benign (Sep 03, 2021) | ||
| 21-43053315-G-A | Classic homocystinuria | Benign (May 10, 2021) | ||
| 21-43053336-A-G | Classic homocystinuria | Benign (May 10, 2021) | ||
| 21-43053340-C-T | Classic homocystinuria • not specified • HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | Conflicting classifications of pathogenicity (Dec 06, 2023) | ||
| 21-43053408-G-A | Classic homocystinuria | Uncertain significance (Jan 12, 2018) | ||
| 21-43053471-C-A | Classic homocystinuria | Uncertain significance (Jan 13, 2018) | ||
| 21-43053471-C-T | Classic homocystinuria | Uncertain significance (Jan 13, 2018) | ||
| 21-43053486-G-A | Classic homocystinuria | Uncertain significance (Apr 06, 2018) | ||
| 21-43053497-G-A | Classic homocystinuria | Benign/Likely benign (May 11, 2021) | ||
| 21-43053575-A-G | Classic homocystinuria | Uncertain significance (Jan 13, 2018) | ||
| 21-43053581-C-T | Classic homocystinuria | Benign (Jun 14, 2018) | ||
| 21-43053584-A-G | Classic homocystinuria | Uncertain significance (Apr 28, 2017) | ||
| 21-43053594-T-C | Classic homocystinuria | Uncertain significance (Jan 13, 2018) | ||
| 21-43053740-C-T | Classic homocystinuria | Uncertain significance (Jan 13, 2018) | ||
| 21-43053748-C-G | Classic homocystinuria | Uncertain significance (Jan 12, 2018) | ||
| 21-43053757-G-C | Classic homocystinuria | Benign (Jan 13, 2018) | ||
| 21-43053772-TGCCAG-T | Homocystinuria | Benign (Jun 14, 2016) | ||
| 21-43053799-C-T | Classic homocystinuria | Benign/Likely benign (Jul 31, 2018) | ||
| 21-43053800-G-A | Classic homocystinuria | Uncertain significance (Jan 12, 2018) | ||
| 21-43053822-CGAA-C | Homocystinuria | Uncertain significance (Jun 14, 2016) | ||
| 21-43053824-AAGG-A | Likely benign (Mar 17, 2021) | |||
| 21-43053846-C-T | not specified • Classic homocystinuria | Benign/Likely benign (Jan 13, 2018) | ||
| 21-43053852-C-T | not specified | Uncertain significance (Jan 12, 2017) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CBS | protein_coding | protein_coding | ENST00000398165 | 15 | 23753 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.0000308 | 0.997 | 125695 | 0 | 52 | 125747 | 0.000207 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.832 | 301 | 344 | 0.874 | 0.0000251 | 3538 |
| Missense in Polyphen | 80 | 114.24 | 0.70027 | 1191 | ||
| Synonymous | -1.11 | 176 | 158 | 1.11 | 0.0000136 | 1091 |
| Loss of Function | 2.64 | 12 | 26.7 | 0.450 | 0.00000127 | 314 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000246 | 0.000241 |
| Ashkenazi Jewish | 0.00139 | 0.00129 |
| East Asian | 0.000224 | 0.000217 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.000202 | 0.000193 |
| Middle Eastern | 0.000224 | 0.000217 |
| South Asian | 0.000229 | 0.000229 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Hydro-lyase catalyzing the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine. This catabolic route allows the elimination of L-methionine and the toxic metabolite L- homocysteine (PubMed:23981774, PubMed:20506325, PubMed:23974653). Also involved in the production of hydrogen sulfide, a gasotransmitter with signaling and cytoprotective effects on neurons (By similarity). {ECO:0000250|UniProtKB:P32232, ECO:0000269|PubMed:20506325, ECO:0000269|PubMed:23974653, ECO:0000269|PubMed:23981774}.;
- Pathway
- Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;Cysteine and methionine metabolism - Homo sapiens (human);Glycine, serine and threonine metabolism - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;S-Adenosylhomocysteine (SAH) Hydrolase Deficiency;Methionine Metabolism;3-Phosphoglycerate dehydrogenase deficiency;Methionine Adenosyltransferase Deficiency;Glycine N-methyltransferase Deficiency;Non Ketotic Hyperglycinemia;Glycine and Serine Metabolism;Hypermethioninemia;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type;Dimethylglycine Dehydrogenase Deficiency;Hyperglycinemia, non-ketotic;Selenoamino Acid Metabolism;Dimethylglycine Dehydrogenase Deficiency;Sarcosinemia;Homocysteine Degradation;Gamma-cystathionase deficiency (CTH);Homocystinuria, cystathionine beta-synthase deficiency;Cystathionine Beta-Synthase Deficiency;Dihydropyrimidine Dehydrogenase Deficiency (DHPD);Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate-Alcohol and Cancer Pathway Hypotheses;Folate Metabolism;Trans-sulfuration pathway;Trans-sulfuration and one carbon metabolism;Vitamin D Receptor Pathway;Amino Acid metabolism;Metabolism of amino acids and derivatives;Glycine Serine metabolism;Metabolism;Methionine Cysteine metabolism;Selenoamino acid metabolism;Cysteine formation from homocysteine;Metabolism of ingested SeMet, Sec, MeSec into H2Se;Methionine and cysteine metabolism;Selenoamino acid metabolism;Putative anti-Inflammatory metabolites formation from EPA;hydrogen sulfide biosynthesis (trans-sulfuration);cysteine biosynthesis/homocysteine degradation (trans-sulfuration);Sulfur amino acid metabolism;cysteine biosynthesis;superpathway of methionine degradation
(Consensus)
Recessive Scores
- pRec
- 0.848
Intolerance Scores
- loftool
- 0.0305
- rvis_EVS
- -0.8
- rvis_percentile_EVS
- 12.53
Haploinsufficiency Scores
- pHI
- 0.532
- hipred
- Y
- hipred_score
- 0.694
- ghis
- 0.549
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.984
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Cbs
- Phenotype
- muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland 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); limbs/digits/tail phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; embryo phenotype; respiratory system phenotype; liver/biliary system phenotype; 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); hematopoietic system phenotype; 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);
Zebrafish Information Network
- Gene name
- cbsb
- Affected structure
- trunk
- Phenotype tag
- abnormal
- Phenotype quality
- bent
Gene ontology
- Biological process
- cysteine biosynthetic process from serine;L-serine metabolic process;L-serine catabolic process;cysteine biosynthetic process via cystathionine;cysteine biosynthetic process;transsulfuration;L-cysteine catabolic process;DNA protection;homocysteine catabolic process;homocysteine metabolic process;oxidation-reduction process;hydrogen sulfide biosynthetic process
- Cellular component
- nucleus;cytoplasm;cytosol
- Molecular function
- cystathionine beta-synthase activity;cysteine synthase activity;protein binding;oxygen binding;enzyme binding;heme binding;pyridoxal phosphate binding;ubiquitin protein ligase binding;identical protein binding;protein homodimerization activity;metal ion binding;nitrite reductase (NO-forming) activity;carbon monoxide binding;nitric oxide binding;modified amino acid binding;S-adenosyl-L-methionine binding