Table 1. Discrimination of derived missense alleles by the NC statistic.

MAC	Variants	N	meanNC	Effect size	95% CI	P
2	coding-synon			baseline
2	missense				(, )
2	benign				(, )
2	possibly damaging				(, )
2	probably damaging				(, )
3	coding-synon			baseline
3	missense				(, )
3	benign				(, )
3	possibly damaging				(, )
3	probably damaging				(, )
4	coding-synon			baseline
4	missense				(, )
4	benign				(, )
4	possibly damaging				(, )
4	probably damaging				(, )
5	coding-synon			baseline
5	missense				(, )
5	benign				(, )
5	possibly damaging				(, )
5	probably damaging				(, )
6	coding-synon			baseline
6	missense				(, )
6	benign				(, )
6	possibly damaging				(, )
6	probably damaging				(, )
2–6	coding-synon			baseline
2–6	missense
2–6	benign
2–6	possibly damaging
2–6	probably damaging

Missense alleles are sub-classified info categories based on PolyPhen-2 predictions. Effect sizes were calculated as standard deviations from the mean of the NC statistic for synonymous variants at the same minor allele count (MAC). Within each MAC class, P-values were calculated by 1-sided Mann-Whitney test. Combined P-values for MAC 2–6 were computed by meta-analysis (Methods).