Table 2 Open in new tab Optimizing with...

Algorithms	N, C-Terminus		Domain linker	S1–S3		Voltage sensor	Pore region
SIFT	≤0.05	64.2	0.350	≤0.05	60.5	0.335	≤0.05	74.8	0.446	≤0.05	88.9	0.254	≤0.05	88.0	0.521
MASS	>1.935	63.4	0.336	>1.935	44.2	0.335	>1.935	79.3	0.534	>1.935	85.9	0.153	>1.935	87.0	0.585
PP2-HDIV	>0.5	65.9	0.400	>0.5	63.4	0.444	>0.5	74.8	0.426	>0.5	87.9	0.125	>0.5	86.1	0.440
PP2-HVAR	>0.5	69.9	0.458	>0.5	69.2	0.463	>0.5	77.0	0.480	>0.5	88.9	0.254	>0.5	86.7	0.482
PROVEAN	≤−2.5	65.9	0.400	≤−2.5	52.9	0.414	≤−2.5	74.8	0.446	≤−2.5	85.9	0.065	≤−2.5	92.2	0.674
SNAP2	>0	64.2	0.350	>0	62.8	0.440	>0	74.8	0.430	>0	90.9	0.406	>0	90.7	0.603
MutPred2	>0.5	72.4	0.483	>0.5	69.8	0.497	>0.5	70.4	0.322	>0.5	89.9	0.286	>0.5	90.1	0.550
I-Mutant 2.0	<0	56.9	0.220	<0	33.1	0.178	<0	60.0	−0.033	<0	76.8	0.019	<0	80.7	0.100
FATHMM-U	<−3.0	69.1	0.382	<−3.0	69.2	0.355	<−3.0	79.3	0.596	<−3.0	65.7	0.241	<−3.0	65.4	0.351
FATHMM-W	<−1.5	48.8	NA	<−1.5	33.1	0.252	<−1.5	64.4	NA	<−1.5	88.9	NA	<−1.5	85.2	NA
After optimization of cutoff value for with stratification
SIFT	=0	72.4	0.455	=0	77.3	0.384	<0.02	78.5	0.418	≤0.02	89.9	0.404	≤0.08	89.8	0.573
MASS	>3.565	82.9	0.677	>3.865	84.9	0.506	>2.91	83.7	0.648	>0.49	90.9	0.406	>1.6	89.2	0.606
PP2-HDIV	>0.922	73.2	0.504	>0.997	80.8	0.469	>0.890	76.3	0.462	>0.872	89.9	0.359	>0.77	87.3	0.531
PP2-HVAR	>0.963	78.0	0.562	>0.947	82.0	0.533	>0.474	78.5	0.516	>0.67	90.9	0.449	0.823	87.3	0.574
PROVEAN	<−2.035	66.7	0.426	≤−6.103	79.7	0.326	<−3.414	81.5	0.586	≤−1.891	88.8	NA	≤−2.197	92.5	0.685
SNAP2	>53	79.7	0.601	>57	86.6	0.589	>62	85.9	0.702	>32	92.9	0.580	>−11	91.0	0.604
MutPred2	>0.720	75.6	0.512	>0.805	87.2	0.600	>0.859	85.2	0.677	>0.700	90.9	0.417	>0.448	90.7	0.574
I-Mutant 2.0	<−0.37	63.4	0.312	<−3.39	77.9	NA	<2.8	64.4	NA	<2.30	88.9	NA	<2.04	85.2	NA
FATHMM-U	<−2.32	70.7	0.420	<−5.73	79.1	0.215	<−2.03	83.7	0.637	<−3.93	88.9	NA	<4.92	85.2	NA
FATHMM-W	<−4.19	73.2	0.474	<−3.84	84.9	0.561	<−4.41	65.2	0.203	<−4.13	88.9	NA	<−3.99	87.7	0.440
Results in total after multiple optimizations
Multiple-step strategy	Acc = 90.5%, sensitivity = 92.6%, specificity = 86.6%, MCC = 0.792 (n = 861)

Algorithms

N, C-Terminus

Domain linker

S1–S3

Voltage sensor

Pore region

Cutoff

Acc (%)

MCC

Cutoff

Acc (%)

MCC

Cutoff

Acc (%)

MCC

Cutoff

Acc (%)

MCC

Cutoff

Acc (%)

MCC

SIFT

≤0.05

64.2

0.350

≤0.05

60.5

0.335

≤0.05

74.8

0.446

≤0.05

88.9

0.254

≤0.05

88.0

0.521

MASS

>1.935

63.4

0.336

>1.935

44.2

0.335

>1.935

79.3

0.534

>1.935

85.9

0.153

>1.935

87.0

0.585

PP2-HDIV

>0.5

65.9

0.400

>0.5

63.4

0.444

>0.5

74.8

0.426

>0.5

87.9

0.125

>0.5

86.1

0.440

PP2-HVAR

>0.5

69.9

0.458

>0.5

69.2

0.463

>0.5

77.0

0.480

>0.5

88.9

0.254

>0.5

86.7

0.482

PROVEAN

≤−2.5

65.9

0.400

≤−2.5

52.9

0.414

≤−2.5

74.8

0.446

≤−2.5

85.9

0.065

≤−2.5

92.2

0.674

SNAP2

64.2

0.350

62.8

0.440

74.8

0.430

90.9

0.406

90.7

0.603

MutPred2

>0.5

72.4

0.483

>0.5

69.8

0.497

>0.5

70.4

0.322

>0.5

89.9

0.286

>0.5

90.1

0.550

I-Mutant 2.0

56.9

0.220

33.1

0.178

60.0

−0.033

76.8

0.019

80.7

0.100

FATHMM-U

<−3.0

69.1

0.382

<−3.0

69.2

0.355

<−3.0

79.3

0.596

<−3.0

65.7

0.241

<−3.0

65.4

0.351

FATHMM-W

<−1.5

48.8

<−1.5

33.1

0.252

<−1.5

64.4

<−1.5

88.9

<−1.5

85.2

After optimization of cutoff value for with stratification

SIFT

72.4

0.455

77.3

0.384

<0.02

78.5

0.418

≤0.02

89.9

0.404

≤0.08

89.8

0.573

MASS

>3.565

82.9

0.677

>3.865

84.9

0.506

>2.91

83.7

0.648

>0.49

90.9

0.406

>1.6

89.2

0.606

PP2-HDIV

>0.922

73.2

0.504

>0.997

80.8

0.469

>0.890

76.3

0.462

>0.872

89.9

0.359

>0.77

87.3

0.531

PP2-HVAR

>0.963

78.0

0.562

>0.947

82.0

0.533

>0.474

78.5

0.516

>0.67

90.9

0.449

0.823

87.3

0.574

PROVEAN

<−2.035

66.7

0.426

≤−6.103

79.7

0.326

<−3.414

81.5

0.586

≤−1.891

88.8

≤−2.197

92.5

0.685

SNAP2

>53

79.7

0.601

>57

86.6

0.589

>62

85.9

0.702

>32

92.9

0.580

>−11

91.0

0.604

MutPred2

>0.720

75.6

0.512

>0.805

87.2

0.600

>0.859

85.2

0.677

>0.700

90.9

0.417

>0.448

90.7

0.574

I-Mutant 2.0

<−0.37

63.4

0.312

<−3.39

77.9

<2.8

64.4

<2.30

88.9

<2.04

85.2

FATHMM-U

<−2.32

70.7

0.420

<−5.73

79.1

0.215

<−2.03

83.7

0.637

<−3.93

88.9

<4.92

85.2

FATHMM-W

<−4.19

73.2

0.474

<−3.84

84.9

0.561

<−4.41

65.2

0.203

<−4.13

88.9

<−3.99

87.7

0.440

Results in total after multiple optimizations

Multiple-step strategy

Acc = 90.5%, sensitivity = 92.6%, specificity = 86.6%, MCC = 0.792 (n = 861)

Algorithms	N, C-Terminus		Domain linker	S1–S3		Voltage sensor	Pore region
SIFT	≤0.05	64.2	0.350	≤0.05	60.5	0.335	≤0.05	74.8	0.446	≤0.05	88.9	0.254	≤0.05	88.0	0.521
MASS	>1.935	63.4	0.336	>1.935	44.2	0.335	>1.935	79.3	0.534	>1.935	85.9	0.153	>1.935	87.0	0.585
PP2-HDIV	>0.5	65.9	0.400	>0.5	63.4	0.444	>0.5	74.8	0.426	>0.5	87.9	0.125	>0.5	86.1	0.440
PP2-HVAR	>0.5	69.9	0.458	>0.5	69.2	0.463	>0.5	77.0	0.480	>0.5	88.9	0.254	>0.5	86.7	0.482
PROVEAN	≤−2.5	65.9	0.400	≤−2.5	52.9	0.414	≤−2.5	74.8	0.446	≤−2.5	85.9	0.065	≤−2.5	92.2	0.674
SNAP2	>0	64.2	0.350	>0	62.8	0.440	>0	74.8	0.430	>0	90.9	0.406	>0	90.7	0.603
MutPred2	>0.5	72.4	0.483	>0.5	69.8	0.497	>0.5	70.4	0.322	>0.5	89.9	0.286	>0.5	90.1	0.550
I-Mutant 2.0	<0	56.9	0.220	<0	33.1	0.178	<0	60.0	−0.033	<0	76.8	0.019	<0	80.7	0.100
FATHMM-U	<−3.0	69.1	0.382	<−3.0	69.2	0.355	<−3.0	79.3	0.596	<−3.0	65.7	0.241	<−3.0	65.4	0.351
FATHMM-W	<−1.5	48.8	NA	<−1.5	33.1	0.252	<−1.5	64.4	NA	<−1.5	88.9	NA	<−1.5	85.2	NA
After optimization of cutoff value for with stratification
SIFT	=0	72.4	0.455	=0	77.3	0.384	<0.02	78.5	0.418	≤0.02	89.9	0.404	≤0.08	89.8	0.573
MASS	>3.565	82.9	0.677	>3.865	84.9	0.506	>2.91	83.7	0.648	>0.49	90.9	0.406	>1.6	89.2	0.606
PP2-HDIV	>0.922	73.2	0.504	>0.997	80.8	0.469	>0.890	76.3	0.462	>0.872	89.9	0.359	>0.77	87.3	0.531
PP2-HVAR	>0.963	78.0	0.562	>0.947	82.0	0.533	>0.474	78.5	0.516	>0.67	90.9	0.449	0.823	87.3	0.574
PROVEAN	<−2.035	66.7	0.426	≤−6.103	79.7	0.326	<−3.414	81.5	0.586	≤−1.891	88.8	NA	≤−2.197	92.5	0.685
SNAP2	>53	79.7	0.601	>57	86.6	0.589	>62	85.9	0.702	>32	92.9	0.580	>−11	91.0	0.604
MutPred2	>0.720	75.6	0.512	>0.805	87.2	0.600	>0.859	85.2	0.677	>0.700	90.9	0.417	>0.448	90.7	0.574
I-Mutant 2.0	<−0.37	63.4	0.312	<−3.39	77.9	NA	<2.8	64.4	NA	<2.30	88.9	NA	<2.04	85.2	NA
FATHMM-U	<−2.32	70.7	0.420	<−5.73	79.1	0.215	<−2.03	83.7	0.637	<−3.93	88.9	NA	<4.92	85.2	NA
FATHMM-W	<−4.19	73.2	0.474	<−3.84	84.9	0.561	<−4.41	65.2	0.203	<−4.13	88.9	NA	<−3.99	87.7	0.440
Results in total after multiple optimizations
Multiple-step strategy	Acc = 90.5%, sensitivity = 92.6%, specificity = 86.6%, MCC = 0.792 (n = 861)

Table 2

Open in new tab

Optimizing with stratification by functional domains for prediction of SCN1A missense variants

Algorithms	N, C-Terminus			Domain linker			S1–S3			Voltage sensor			Pore region
Algorithms	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC
SIFT	≤0.05	64.2	0.350	≤0.05	60.5	0.335	≤0.05	74.8	0.446	≤0.05	88.9	0.254	≤0.05	88.0	0.521
MASS	>1.935	63.4	0.336	>1.935	44.2	0.335	>1.935	79.3	0.534	>1.935	85.9	0.153	>1.935	87.0	0.585
PP2-HDIV	>0.5	65.9	0.400	>0.5	63.4	0.444	>0.5	74.8	0.426	>0.5	87.9	0.125	>0.5	86.1	0.440
PP2-HVAR	>0.5	69.9	0.458	>0.5	69.2	0.463	>0.5	77.0	0.480	>0.5	88.9	0.254	>0.5	86.7	0.482
PROVEAN	≤−2.5	65.9	0.400	≤−2.5	52.9	0.414	≤−2.5	74.8	0.446	≤−2.5	85.9	0.065	≤−2.5	92.2	0.674
SNAP2	>0	64.2	0.350	>0	62.8	0.440	>0	74.8	0.430	>0	90.9	0.406	>0	90.7	0.603
MutPred2	>0.5	72.4	0.483	>0.5	69.8	0.497	>0.5	70.4	0.322	>0.5	89.9	0.286	>0.5	90.1	0.550
I-Mutant 2.0	<0	56.9	0.220	<0	33.1	0.178	<0	60.0	−0.033	<0	76.8	0.019	<0	80.7	0.100
FATHMM-U	<−3.0	69.1	0.382	<−3.0	69.2	0.355	<−3.0	79.3	0.596	<−3.0	65.7	0.241	<−3.0	65.4	0.351
FATHMM-W	<−1.5	48.8	NA	<−1.5	33.1	0.252	<−1.5	64.4	NA	<−1.5	88.9	NA	<−1.5	85.2	NA
After optimization of cutoff value for with stratification
SIFT	=0	72.4	0.455	=0	77.3	0.384	<0.02	78.5	0.418	≤0.02	89.9	0.404	≤0.08	89.8	0.573
MASS	>3.565	82.9	0.677	>3.865	84.9	0.506	>2.91	83.7	0.648	>0.49	90.9	0.406	>1.6	89.2	0.606
PP2-HDIV	>0.922	73.2	0.504	>0.997	80.8	0.469	>0.890	76.3	0.462	>0.872	89.9	0.359	>0.77	87.3	0.531
PP2-HVAR	>0.963	78.0	0.562	>0.947	82.0	0.533	>0.474	78.5	0.516	>0.67	90.9	0.449	0.823	87.3	0.574
PROVEAN	<−2.035	66.7	0.426	≤−6.103	79.7	0.326	<−3.414	81.5	0.586	≤−1.891	88.8	NA	≤−2.197	92.5	0.685
SNAP2	>53	79.7	0.601	>57	86.6	0.589	>62	85.9	0.702	>32	92.9	0.580	>−11	91.0	0.604
MutPred2	>0.720	75.6	0.512	>0.805	87.2	0.600	>0.859	85.2	0.677	>0.700	90.9	0.417	>0.448	90.7	0.574
I-Mutant 2.0	<−0.37	63.4	0.312	<−3.39	77.9	NA	<2.8	64.4	NA	<2.30	88.9	NA	<2.04	85.2	NA
FATHMM-U	<−2.32	70.7	0.420	<−5.73	79.1	0.215	<−2.03	83.7	0.637	<−3.93	88.9	NA	<4.92	85.2	NA
FATHMM-W	<−4.19	73.2	0.474	<−3.84	84.9	0.561	<−4.41	65.2	0.203	<−4.13	88.9	NA	<−3.99	87.7	0.440
Results in total after multiple optimizations
Multiple-step strategy	Acc = 90.5%, sensitivity = 92.6%, specificity = 86.6%, MCC = 0.792 (n = 861)

Algorithms	N, C-Terminus			Domain linker			S1–S3			Voltage sensor			Pore region
Algorithms	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC	Cutoff	Acc (%)	MCC
SIFT	≤0.05	64.2	0.350	≤0.05	60.5	0.335	≤0.05	74.8	0.446	≤0.05	88.9	0.254	≤0.05	88.0	0.521
MASS	>1.935	63.4	0.336	>1.935	44.2	0.335	>1.935	79.3	0.534	>1.935	85.9	0.153	>1.935	87.0	0.585
PP2-HDIV	>0.5	65.9	0.400	>0.5	63.4	0.444	>0.5	74.8	0.426	>0.5	87.9	0.125	>0.5	86.1	0.440
PP2-HVAR	>0.5	69.9	0.458	>0.5	69.2	0.463	>0.5	77.0	0.480	>0.5	88.9	0.254	>0.5	86.7	0.482
PROVEAN	≤−2.5	65.9	0.400	≤−2.5	52.9	0.414	≤−2.5	74.8	0.446	≤−2.5	85.9	0.065	≤−2.5	92.2	0.674
SNAP2	>0	64.2	0.350	>0	62.8	0.440	>0	74.8	0.430	>0	90.9	0.406	>0	90.7	0.603
MutPred2	>0.5	72.4	0.483	>0.5	69.8	0.497	>0.5	70.4	0.322	>0.5	89.9	0.286	>0.5	90.1	0.550
I-Mutant 2.0	<0	56.9	0.220	<0	33.1	0.178	<0	60.0	−0.033	<0	76.8	0.019	<0	80.7	0.100
FATHMM-U	<−3.0	69.1	0.382	<−3.0	69.2	0.355	<−3.0	79.3	0.596	<−3.0	65.7	0.241	<−3.0	65.4	0.351
FATHMM-W	<−1.5	48.8	NA	<−1.5	33.1	0.252	<−1.5	64.4	NA	<−1.5	88.9	NA	<−1.5	85.2	NA
After optimization of cutoff value for with stratification
SIFT	=0	72.4	0.455	=0	77.3	0.384	<0.02	78.5	0.418	≤0.02	89.9	0.404	≤0.08	89.8	0.573
MASS	>3.565	82.9	0.677	>3.865	84.9	0.506	>2.91	83.7	0.648	>0.49	90.9	0.406	>1.6	89.2	0.606
PP2-HDIV	>0.922	73.2	0.504	>0.997	80.8	0.469	>0.890	76.3	0.462	>0.872	89.9	0.359	>0.77	87.3	0.531
PP2-HVAR	>0.963	78.0	0.562	>0.947	82.0	0.533	>0.474	78.5	0.516	>0.67	90.9	0.449	0.823	87.3	0.574
PROVEAN	<−2.035	66.7	0.426	≤−6.103	79.7	0.326	<−3.414	81.5	0.586	≤−1.891	88.8	NA	≤−2.197	92.5	0.685
SNAP2	>53	79.7	0.601	>57	86.6	0.589	>62	85.9	0.702	>32	92.9	0.580	>−11	91.0	0.604
MutPred2	>0.720	75.6	0.512	>0.805	87.2	0.600	>0.859	85.2	0.677	>0.700	90.9	0.417	>0.448	90.7	0.574
I-Mutant 2.0	<−0.37	63.4	0.312	<−3.39	77.9	NA	<2.8	64.4	NA	<2.30	88.9	NA	<2.04	85.2	NA
FATHMM-U	<−2.32	70.7	0.420	<−5.73	79.1	0.215	<−2.03	83.7	0.637	<−3.93	88.9	NA	<4.92	85.2	NA
FATHMM-W	<−4.19	73.2	0.474	<−3.84	84.9	0.561	<−4.41	65.2	0.203	<−4.13	88.9	NA	<−3.99	87.7	0.440
Results in total after multiple optimizations
Multiple-step strategy	Acc = 90.5%, sensitivity = 92.6%, specificity = 86.6%, MCC = 0.792 (n = 861)

The data in bold highlights the best tool for prediction. Acc, accuracy; MCC, Matthews correlation coefficient; NA, not applicable.

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