RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2941C>T (p.Arg981Ter) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3221G>A) is present in 14 XX and 7 XY individuals in gnomAD v4 (0.0043%) (not sufficient to meet BS1 criteria). The p.Arg981Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (not sufficient to meet PVS1 criteria). Additionally, the p.Arg981Ter variant is observed in at least 6 unaffected individuals (internal database - Invitae, internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Arg981Ter variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS2).