Sep 18, 2014

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

BioRxiv : the Preprint Server for Biology
Chunlei WuSvetlana Gorokhova

Abstract

Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. In order to explore an often overlooked splicing effect of missense variants, we developed the functional assay ("minigene") for the majority of exons of CAPN3, the gene responsible for Limb Girdle Muscular Dystrophy (LGMD). By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon/intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the ACMG classification of seven of them when results of the "minigene" functional assay were taken into account. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a dis...Continue Reading

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Mentioned in this Paper

Abnormal Fragmented Structure
Environmental Infrastructure
Genes
Aggregation
Ncbi Taxonomy
Bio-Informatics
Universal Protein Resource
Pharmacologic Substance
Mandibular Left Third Molar Mesial Hemisection
Abnormal Coordination

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