Somatic mutations in CALR and predicted consequences. (A) Terminal exon (exon 9) of the gene CALR. The 2 most common mutations, found in 85% of cases, are a 52-bp deletion (Type 1; L367fs*46) or a 5-bp insertion of TTGTC (Type 2; K385fs*47) shown above the exon in blue. Rarer mutations comprise other deletions, insertions, or complex mutations and are shown below the exon. Grey bars represent deleted DNA and black letters show inserted bases. (B) Wild-type amino acid peptide sequence of the CALR C-terminus and the predicted sequence of the 2 most common mutations. All mutations lead to a 1-bp shift to the reading frame, resulting in the generation of a common novel terminal peptide sequence (shaded in blue). (C) Predicted effects on protein structure. Wild-type CALR on the left has a C-domain rich in calcium-binding sites and a KDEL endoplasmic reticulum retention motif, both of which are predicted to be lost in mutant CALR, as shown on the right.