9 CHAPTER 9 194 important functions of CaV channels, it is not surprising that genetic variation in CACNA1x genes is not well-tolerated; the residual variation intolerance scores for these genes are high (Table 1).24 Figure 1 The voltage-gated calcium channel (VGCC) family of proteins The α1 subunits can be divided into three subclasses according to their amino acid sequence identity, as shown in the dendrogram. CaV1 and CaV2 channels are high-voltage-activated (HVA), whereas CaV3 channels are lowvoltage-activated (LVA). The genes encoding the respective α1 subunit are provided as well as the type of current the respective channel type produces. The Schematic is based upon Perez-Reyes and Dolphin.22, 23 Table 1 Intolerance scores CACNA1x genes. Gene RVIS %ExAC RVIS %ExAC Lof FDR %ExAC v2 RVIS Edge case (%OE-ratio) CACNA1A -1.78 (2.27%) 1.68% 1.35 x 10-10 -2.20 (2.45%) N (4.41%) CACNA1B NA (NA) 0.79% 1.48 x 10-5 -2.34 (2.17%) N (10.98%) CACNA1C -2.09 (1.57%) 3.51% 9.23 x 10-8 -1.53 (5.77%) N (4.20%) CACNA1D -3.51 (0.32%) 0.39% 1.64 x 10-13 -3.37 (0.72%) N (11.785) CACNA1E -2.71 (0.71%) 3.34% 8.29 x 10-18 -1.88 (3.59%) N (5.73%) CACNA1F -0.83 (11.53%) 12.28% 1.03 x 10-4 0.02 (52.82%) N (45.93%) CACNA1G -2.37 (1.11%) 1% 2.45 x 10-8 -2.08 (2.85%0 N (13.56%) CACNA1H -2.06 (1.63%) 25.99% 1.79 x 10-9 -0.03 (48.18%) N (13.68%) CACNA1I -0.83 (11.55%) 3.96% 4.29 x 10-6 -1.90 (3.52%) N (7.79%) CACNA1S -1.21 (5.71%) 61.36% 8.21 x 10-5 0.52 (72.65%) N (41.68%) RVIS = Residual variation intolerance score (is a gene score based module intended to help in the interpretation of human sequence data); %ExAC RVIS = RVIS v3, constructed on the ExAC data release; ExAC LoF FDR = FDR-adjusted p-value reflects the significance of the departure from the expected rate of LoF variants; %ExAC v2 RVIS = RVIS v4, constructed on the ExAC v2 data release; Edge Case = Edge case genes. The OE-ratio is based on ExaC v2 data release.
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