Shallow whole-genome sequencing to infer copy number alterations (CNAs) in the human genome is rapidly becoming the method par excellence for routine diagnostic use. Numerous tools exist to deduce aberrations from massive parallel sequencing data, yet most are optimized for research and often fail to redeem paramount needs in a clinical setting. Optimally, a read depth-based analytical software should be able to deal with single-end and low-coverage data—this to make sequencing costs feasible. Other important factors include runtime, applicability to a variety of analyses and overall performance. We compared the most important aspect, being normalization, across six different CNA tools, selected for their assumed ability to satisfy the latter needs. In conclusion, WISECONDOR, which uses a within-sample normalization technique, undoubtedly produced the best results concerning variance, distributional assumptions and basic ability to detect true variations. Nonetheless, as is the case with every tool, WISECONDOR has limitations, which arise through its exclusiveness for non-invasive prenatal testing. Therefore, this work presents WisecondorX in addition, an improved WISECONDOR that enables its use for varying types of applications. WisecondorX is freely available at https://github.com/CenterForMedicalGeneticsGhent/WisecondorX.