Background: Primary aldosteronism (PA) results from both unilateral and bilateral adrenal disease. Unilateral disease is most often caused by aldosterone-producing adenomas (APAs). We recently identified aldosterone-driver somatic mutations in approximately 90% of APAs using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, we analyzed DNA from APA samples found to be mutation negative. Methods: Formalin-fixed paraffin-embedded tissue samples from PA patients who underwent adrenalectomy were studied. Genomic DNA was isolated from 118 APAs (identified by CYP11B2 IHC). Next generation sequencing (NGS) was performed to identify known aldosterone-driver mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D. APA DNA that was mutation negative and the adjacent normal adrenal tissue DNA were subjected to Whole Exome Sequencing (WES). Results: Targeted NGS and WES detected two variants in the voltage-gated chloride channel ClC-2 (encoded by CLCN2), which were confirmed by Sanger sequencing. One of the CLCN2 mutations (p.Gly24Asp) was identical to that previously found to cause germline early-onset PA. The second CLCN2 mutation, which would affect the same region of the protein, was an unreported PA mutation (p.Met22fs). The presence of these variants in two tumors suggests that CLCN2 mutations as a cause of APAs are rare with an approximate prevalence of 1.7% (2/118 APAs). Conclusion: In this study, we identified somatic mutations in CLCN2, in two of 118 APAs. Germline variants in this gene have previously been shown to cause of familial hyperaldosteronism type II and the current findings indicate that similar mutations cause a small proportion of APAs. These findings also indicate that WES of CYP11B2-guided mutation negative APAs can help determine rarer genetic causes of sporadic PA.