ArticleGenetics in medicine : official journal of the American College of Medical Genetics2016
CADD score has limited clinical validity for the identification of pathogenic variants in noncoding regions in a hereditary cancer panel.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- Review
- The role of non-coding variants in hereditary cancer syndromes: mechanistic insights and clinical implications.Annals of medicine and surgery (2012) · 2026Review
- Alteplase and Angioedema: Can Clinical Exome Sequencing Redefine the Paradigm?Life (Basel, Switzerland) · 2026Article
- Genome region aware CADD thresholds for noncoding variant prioritization.NAR genomics and bioinformatics · 2025Article
- UCP3 gene variants and obesity in a Pakistani sample population.Scientific reports · 2025Article
- CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions.Nucleic acids research · 2024Article
- Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts.Human genetics · 2023Article
- Genetic variant annotation scores in congenital long QT syndrome.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2023Article
- Article
- The Genetic Landscape of Familial Pulmonary Fibrosis.American journal of respiratory and critical care medicine · 2023Article
- GRHL2 and AP2a coordinate early surface ectoderm lineage commitment during development.iScience · 2023Article
- Evaluating the Utility of REVEL and CADD for Interpreting Variants in Amyotrophic Lateral Sclerosis Genes.Human mutation · 2023Article
- A novel compound heterozygous mutation ofFrontiers in neurology · 2023Article
- VPMBench: a test bench for variant prioritization methods.BMC bioinformatics · 2021Article
- Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes.Nature medicine · 2021Article
- Biomedical Data Commons (BMDC) prioritizes B-lymphocyte non-coding genetic variants in Type 1 Diabetes.PLoS computational biology · 2021Article
- Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance.The Journal of experimental medicine · 2021Article
- Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores.Genome medicine · 2021Article
- Re-analysis of Genetic Risks for Chronic Fatigue Syndrome From 23andMe Data Finds Few Remain.Frontiers in pediatrics · 2021Article
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7 authors.
Funding
Abstract
purposeSeveral in silico tools have been shown to have reasonable research sensitivity and specificity for classifying sequence variants in coding regions. The recently developed combined annotation-dependent depletion (CADD) method generates predictive scores for single-nucleotide variants (SNVs) in all areas of the genome, including noncoding regions. We sought for non-coding variants to determine the clinical validity of common CADD scores.
methodsWe evaluated 12,391 unique SNVs in 624 patient samples submitted for germ-line mutation testing in a cancer-related gene panel. Stratifying by genomic region, we compared the distributions of CADD scores of rare SNVs, SNVs common in our patient population, and the null distribution of all possible SNVs.
resultsThe median CADD scores of intronic and nonsynonymous variants were significantly different between rare and common SNVs (P < 0.0001). Despite these different distributions, no individual variants could be identified as plausibly causative among the rare intronic variants with the highest scores. The receiver-operating characteristics (ROC) area under the curve (AUC) for noncoding variants is modest, and the positive predictive value of CADD for intronic variants in panel testing was found to be 0.088.
conclusionFocused in silico scoring systems with much higher predictive value will be necessary for clinical genomic applications.Genet Med 18 12, 1269-1275.
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