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As next generation sequencing (NGS) technology has already become a regular fixture in research, it is now time for clinical environments to also reap the benefits of such technology. Indeed, the rich promise of NGS has the potential to be translated into improved patient care. However, there is still doubt about the widespread use of NGS in clinical diagnostics. Before implementation, there must be consensus on which analytical pipeline to use, with follow-up confirmation of variants with the gold standard: Sanger sequencing. Here, we present a NGS analytical pipeline that has complete agreement on 341 variants with Sanger sequencing and that is already being used in our clinical diagnostic laboratory in the National Health Service England for the regular screening of inherited, pathogenic variants. Details on our NGS and other services can be found at http://www.sheffieldchildrens.nhs.uk/our-services/sheffield-diagnostic-genetics-service/. Our pipeline broadly follows the ‘best practices’ guidelines set by the GATK at the Broad Institute, with a novel added approach involving randomly selecting subsets of reads and later merging variants called from each. This allows for falsenegatives to be eliminated with a high level of confidence. Moreover, modeling reduced depth of coverage reveals that 30X is the point at which false-positives are eliminated with >99.9% confidence. Our results allude to a fine balance between read-depth and error, and we believe that our pipeline will increase confidence in NGS and permit its gradual enrollment in clinical diagnostic laboratories.