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Background  The clinical significance of  SPINK1  intronic variants in chronic pancreatitis has been previously assessed by various approaches including a cell culture-based full-length gene assay. A close correlation between the results of this assay and in silico splicing prediction was apparent. However, until now, a clinical diagnostic pipeline specifically designed to classify  SPINK1  intronic variants accurately and efficiently has been lacking. Herein, we present just such a pipeline and explore its efficacy and potential utility in potentiating the classification of newly described  SPINK1  intronic variants.    Results  We confirm a close correlation between in silico splicing prediction and results from the cell culture-based full-length gene assay in the context of three recently reported pathogenic  SPINK1  intronic variants. We then integrated in silico splicing prediction and the full-length gene assay into a stepwise approach and tested its utility in the classification of two novel datasets of  SPINK1  intronic variants. The first dataset comprised 16 deep intronic variants identified in 52 genetically unexplained Chinese chronic pancreatitis patients by sequencing the entire intronic sequence of the  SPINK1  gene. The second dataset comprised five novel rare proximal intronic variants identified through the routine analysis of the  SPINK1  gene in French pancreatitis patients. Employing a minor allele frequency of > 5% as a population frequency filter, 6 of the 16 deep intronic variants were immediately classified as benign. In silico prediction of the remaining ten deep intronic variants and the five rare proximal intronic variants with respect to their likely impact on splice site selection suggested that only one proximal intronic variant, c.194 + 5G > A, was likely to be of functional significance. Employing the cell culture-based full-length gene assay, we functionally analyzed c.194 + 5G > A, together with seven predicted non-functional variants, thereby validating their predicted effects on splicing in all cases.    Conclusions  We demonstrated the accuracy and efficiency of in silico prediction in combination with the cell culture-based full-length gene assay for the classification of  SPINK1  intronic variants. Based upon these findings, we propose an operational pipeline for classifying  SPINK1  intronic variants in the clinical diagnostic setting.    Electronic supplementary material  The online version of this article (10.1186/s40246-019-0193-7) contains supplementary material, which is available to authorized users.

Toward a clinical diagnostic pipeline for SPINK1 intronic variants