{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T19:56:18Z","timestamp":1767902178905,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T00:00:00Z","timestamp":1721779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>CTNNB1 pathogenic variants are related to the improper functioning of the WNT\/\u03b2-catenin pathway, promoting the development of different types of cancer of somatic origin. Bioinformatics analyses of genetic variation are a great tool to understand the possible consequences of these variants on protein structure and function and their probable implication in pathologies. The objective of this study is to describe the impact of the missense variants of uncertain significance (VUS) of the CTNNB1 gene on structure and function of the \u03b2-catenin protein. The CTNNB1 variants were obtained from the GnomAD v2.1.1 database; subsequently, a bioinformatic analysis was performed using the VarSome, UCSC Genome Browser, UniProt, the Kinase Library database, and DynaMut2 platforms to evaluate clinical significance, gene conservation, consensus sites for post-translational modifications, and the dynamics and stability of proteins. The GnomAD v2.1.1 database included 826 variants of the CTNNB1 gene, of which 385 were in exons and exon\/intron boundaries. Among these variants, 214 were identified as missense, of which 146 were classified as VUS. Notably, 12 variants were in proximity to consensus sites for post-translational modifications (PTMs). The in silico analysis showed a slight tendency towards probably pathogenic for c.59C&gt;T (p.Ala20Val) and c.983T&gt;C (p.Met328Thr) missense VUS. These findings provide possible functional implications of these variants in some types of cancer.<\/jats:p>","DOI":"10.3390\/genes15080972","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T06:11:36Z","timestamp":1721887896000},"page":"972","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Silico Analysis of the Missense Variants of Uncertain Significance of CTNNB1 Gene Reported in GnomAD Database"],"prefix":"10.3390","volume":"15","author":[{"given":"Arturo","family":"Caballero-Avenda\u00f1o","sequence":"first","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana e Instituto de Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3848-8892","authenticated-orcid":false,"given":"Melva","family":"Guti\u00e9rrez-Angulo","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana e Instituto de Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico"},{"name":"Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Tepatitl\u00e1n de Morelos 47600, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8875-5624","authenticated-orcid":false,"given":"Mar\u00eda de la Luz","family":"Ayala-Madrigal","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana e Instituto de Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7555-9851","authenticated-orcid":false,"given":"Jos\u00e9 Miguel","family":"Moreno-Ortiz","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana e Instituto de Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8005-1304","authenticated-orcid":false,"given":"Anah\u00ed","family":"Gonz\u00e1lez-Mercado","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana e Instituto de Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Peregrina-Sandoval","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular del Departamento de Biolog\u00eda Celular y Molecular, Centro Universitario de Ciencias Biol\u00f3gicas y Agropecuarias, Zapopan 45200, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D9","DOI":"10.1093\/nar\/gkz899","article-title":"Database resources of the National Center for Biotechnology Information","volume":"48","author":"Sayers","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_2","first-page":"8","article-title":"Mutation hotspots in the \u03b2-catenin gene: Lessons from the human cancer genome databases","volume":"42","author":"Kim","year":"2019","journal-title":"Mol. Cells"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nbt.3391","article-title":"Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity","volume":"34","author":"Chang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhuang, W., Ye, T., Wang, W., Song, W., and Tan, T. (2023). CTNNB1 in neurodevelopmental disorders. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1143328"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41586-022-05575-3","article-title":"An atlas of substrate specificities for the human serine\/threonine kinome","volume":"613","author":"Johnson","year":"2023","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: The universal protein knowledgebase in 2021","volume":"49","author":"Bateman","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"D512","DOI":"10.1093\/nar\/gku1267","article-title":"PhosphoSitePlus, 2014: Mutations, PTMs and recalibrations","volume":"43","author":"Hornbeck","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The Human Genome Browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1002\/pro.3942","article-title":"DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations","volume":"30","author":"Rodrigues","year":"2021","journal-title":"Protein Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Corso, G., Corso, F., Bellerba, F., Carneiro, P., Seixas, S., Cioffi, A., La Vecchia, C., Magnoni, F., Bonanni, B., and Veronesi, P. (2021). Geographical distribution of e-cadherin germline mutations in the context of diffuse gastric cancer: A systematic review. Cancers, 13.","DOI":"10.3390\/cancers13061269"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.yexcr.2013.11.021","article-title":"\u03b2-Catenin is O-GlcNAc glycosylated at Serine 23: Implications for \u03b2-catenin\u2019s subcellular localization and transactivator function","volume":"321","author":"Ha","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gky1015","article-title":"COSMIC: The Catalogue of Somatic Mutations in Cancer","volume":"47","author":"Tate","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vasovcak, P., Pavlikova, K., Sedlacek, Z., Skapa, P., Kouda, M., Hoch, J., and Krepelova, A. (2011). Molecular genetic analysis of 103 sporadic colorectal tumours in Czech patients. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024114"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Stamos, J.L., and Weis, W.I. (2013). The \u03b2-catenin destruction complex. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a007898"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.canlet.2020.12.032","article-title":"The human VRK1 chromatin kinase in cancer biology","volume":"503","author":"Lazo","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e100847","DOI":"10.15252\/embj.2018100847","article-title":"Strong anion exchange-mediated phosphoproteomics reveals extensive human non-canonical phosphorylation","volume":"38","author":"Hardman","year":"2019","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1016\/j.gpb.2023.03.007","article-title":"A Review of Machine Learning and Algorithmic Methods for Protein Phosphorylation Site Prediction","volume":"21","author":"Esmaili","year":"2023","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_21","first-page":"1257","article-title":"Gene mutation analysis of sinonasal lymphomas in Indonesia","volume":"15","author":"Kurniawan","year":"2006","journal-title":"Oncol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.1158\/0008-5472.CAN-23-0816","article-title":"Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal","volume":"83","author":"Kundra","year":"2023","journal-title":"Cancer Res."},{"key":"ref_23","first-page":"Unit7.20","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"7","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Van der Wal, T., and van Amerongen, R. (2020). Walking the tight wire between cell adhesion and WNT signalling: A balancing act for \u03b2-catenin. Open Biol., 10.","DOI":"10.1098\/rsob.200267"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5492","DOI":"10.18632\/oncotarget.23695","article-title":"Exon 3 mutations of CTNNB1 drive tumorigenesis: A review","volume":"9","author":"Gao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1042\/BCJ20220251","article-title":"A global view of the human post-translational modification landscape","volume":"480","author":"Kitamura","year":"2023","journal-title":"Biochem. J."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/972\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:22:10Z","timestamp":1760109730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,24]]},"references-count":26,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["genes15080972"],"URL":"https:\/\/doi.org\/10.3390\/genes15080972","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,24]]}}}