Variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2

Jorgens Prado, Mayara; Ligabue-Braun, Rodrigo; Zaha, Arnaldo; Rossetti, Maria Lucia Rosa; Pandey, Amit V (2022). Variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2. Frontiers in Pharmacology, 13, p. 931089. Frontiers 10.3389/fphar.2022.931089

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CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia (CAH) cases, a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provide critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Here, we analyzed the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of CYP21A2. SNVs of CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. All SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy of between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews’ correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). From our analysis, we identified four predictors of CYP21A2 variant pathogenicity with good performance, CADD, ConSurf, DANN, and PolyPhen2. These results can be used for future analysis to infer the impact of uncharacterized SNVs in CYP21A2.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders

UniBE Contributor:

Jorgens Prado, Mayara, Pandey, Amit Vikram


600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology






[73] Swiss Government Excellence Scholarship




Amit Vikram Pandey

Date Deposited:

06 Oct 2022 14:58

Last Modified:

08 Jan 2023 02:07

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