Herein, we describe two related patients presenting with HIGM2 disease due to a novel heterozygous AICDA variant (c.566_568delinsAA; L189X) that leads to expression of truncated AID protein and impairs both CSR and SHM, thus further refining the correlation between AICDA genotype and SHM phenotype. The gene discussed is AICDA; the disease is hyper-IgM syndrome type 2.