Expanding ACMG variant classification guidelines into a general framework

Table 1 Some general information about the four CP genes

Gene (encoded protein)	Year of discovery	Discovery approach	Reference mRNA sequence	Coding sequence (bp)	Protein sequence (aa)	Protein tissue expression^a	Cell type expression in exocrine pancreas	Functional categories of pathologically relevant variants^b	o/e score of pLoF variants (95% CI)^c
PRSS1 (cationic trypsinogen)	1996	Positional cloning [23]	NM_002769.5	744	247	Specifically expressed in exocrine pancreas	Acinar	GoF (majority); GoP (minority)	1.31 (0.86–1.86)
CFTR (cystic fibrosis transmembrane conductance regulator)	1998	Candidate gene approach based upon the role of CFTR in cystic fibrosis [28, 29]	NM_000492.4	4443	1480	Highly expressed in exocrine pancreas and kidney; medially expressed in salivary gland, duodenum and small intestine	Ductal and centroacinar	LoF	1.09 (0.91–1.31)
SPINK1 (pancreatic secretory trypsin inhibitor)	2000	Candidate gene approach stimulated by the PRSS1 finding [30]	NM_001379610.1	240	79	Highly expressed in exocrine pancreas, gastrointestinal tract, urinary bladder and appendix	Acinar	LoF	0.24 (0.09–1.13)
CTRC (chymotrypsin C)	2008	Candidate gene approach stimulated by the PRSS1 finding [31, 32]	NM_007272.3	807	268	Specifically expressed in exocrine pancreas	Acinar	LoF (majority); GoP (minority)	1.15 (0.78–1.69)

aa amino acid, bp base-pair, CI confidence interval, CP chronic pancreatitis, GoF gain-of-function, GoP gain-of-proteotoxicity, LoF loss-of-function, o/e observed/expected, pLoF predicted loss-of-function
^aIn accordance with the Human Protein Atlas (https://www.proteinatlas.org/) [73]
^bSee text for details
^cIn accordance with gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) [74]

ISSN: 1479-7364