Fig. 2: Distribution of CMTR2 missense mutations within the NCC cohort.

a Top: Lollipop plot showing CMTR2 mutations identified in the CMTR2 cluster in the NCC cohort. Bottom: Domain structure of the CMTR2 protein aligned with the amino acid positions shown in the lollipop plot above. b Predicted CMTR2 protein structure. The N-terminal region harboring the catalytic domain is shown in cyan and the C-terminal region harboring the non-catalytic domain is shown in green. The CMTR2 missense mutations in the CMTR2 cluster of the NCC cohort are shown in red. c Superimposition of the mean structures obtained from five 1-μs MD simulations of WT CMTR2 (green) and the K117N mutant (magenta) complexed with an mRNA substrate and SAM. The main chains of the protein and mRNA are shown as a transparent ribbon model, while the catalytic K-D-K motif residues (K/N117, D235, and K275), SAM, and the second transcribed nucleotide of the mRNA are highlighted with stick models. Black and red arrows indicate the distances between the amino nitrogen of K/N117 and the 2’-O position of the second transcribed nucleotide, respectively. d All possible missense mutations in CMTR2, with AM pathogenicity scores (y-axis) plotted against amino acid positions (x-axis). Large dots represent CMTR2 mutations in the TCGA or NCC LADC cohort; mutations in cases within and outside the CMTR2 cluster in the t-SNE plot are shown in red and blue, respectively. The bar chart above the scatter plot shows the frequency of likely pathogenic mutations at each amino acid position. e Predicted protein structure of CMTR2 with the 5′ RNA cap (green) and SAM (yellow). Left: cartoon; right: surface representation. The color of each residue represents the average AM pathogenicity score. Residues are shown in red (likely pathogenic), blue (likely benign), or gray (ambiguous).