Abstract Background Alternative splicing (AS)‐related single nucleotide polymorphisms (SNPs) are associated with risk of cancers, but the potential mechanism has not been fully elucidated. Methods Two‐stage case–control studies comprising 1630 cases and 2504 controls were conducted to investigate the association between the AS‐SNPs and bladder cancer susceptibility. A series of assays were used to evaluate the functional effect of AS‐SNPs on bladder cancer risk. Results We observed that SNP rs558814 A>G located in lncRNA BCLET (Bladder Cancer Low‐Expressed Transcript, ENSG00000245498) can decrease the risk of bladder cancer (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.76–0.92, p = 3.26 × 10−4). Additionally, the G allele of rs558814 had transcriptional regulatory effects and facilitated the expression of BCLET transcripts, including BCLET‐long and BCLET‐short. We also found decreased BCLET expression in bladder cancer tissues and cells, and BCLET transcript upregulation substantially inhibited tumor growth of both bladder cancer cells and xenograft models. Mechanistically, BCLET recognized and regulated AS of MSANTD2 to participate in bladder carcinogenesis, preferentially promoting the production of MSANTD2‐004. Conclusions SNP rs558814 was associated with the expression of BCLET, which mainly increased the expression of MSANTD2‐004 through AS of MSANTD2.
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