Table 2.

Most significantly associated rare variants in the family-based association test and their predicted pathogenicity^*

Chr:BP (hg19)	dbSNP identifier	Gene	Reference allele/ alternative allele	Variant type	PolyPhen	CADD Phred score	DANN score	Alternative allele count†	Pedigree (per-family LOD)
10:52005095	rs116049719	ASAH2‡	G/A	Nonsense	—	35	0.9974	9	131 (0.31) 18 (0.42)§ 1 (0.68) 74 (−0.03)
10:55566719	rs570828018	PCDH15	G/A	Missense	Damaging	19.18	0.9984	5	138 (0.43)¶
10:55581787	Novel	PCDH15	T/A	Missense	Benign	23	0.9664	5	18 (0.42)§
10:64967951	rs139722368	JMJD1C	CTAAAC/−	Indel	—	19.05	—	15	129 (0.24) 138 (0.43)¶ 19 (−0.124)
10:64974380	rs41274074	JMJD1C	G/C	Missense	Benign	15.64	0.8880	15	129 (0.24) 138 (0.43)¶ 19 (−0.124)
10:61815652	rs780899852	ANK3	G/C	Missense	Damaging	24.3	0.9927	5	18 (0.42)§
10:64913602	rs62623680	NRBF2	A/G	Missense	Damaging	28.3	0.9980	6	17 (0.57)

CADD = Combined Annotation Dependent Depletion; Chr:BP (hg19) = the chromosome (chr) and base pair (BP) position of each variant, based on Genome Reference Consortium Human Build 37 (GRCh37/hg19); DANN = Deleterious Annotation of genetic variants using Neural Networks; dbSNP ID = SNP identifier; LOD = logarithm of the odds (for linkage); PolyPhen = polymorphism phenotyping, functional prediction of SNP impact on protein product; SNP = single nucleotide polymorphism.

^*Pathogenicity prediction is presented for missense variants using PolyPhen, the CADD Phred scaled score and DANN scores. A CADD Phred scaled score⁴² of 20 means that the variant is among the top 1% of deleterious variants in the human genome, and a score of 30 means that the variant is in the top 0.1%. For DANN,⁴³ a score of 0.96 identifies 92.1% of pathogenic variations from ClinVar (www.ncbi.nlm.nih.gov/clinvar) and 18.1% of false-positive benign variations; values greater than 0.98 predict protein-disrupting or -altering variants. Positive values for the per-family LOD score indicate a positive contribution to the linkage signal from each family carrying that variant.

^†Total number of alternative alleles observed across 117 sequenced individuals.

^‡Genes not expressed in the brain (defined by reads per kilobase per million [RPKM] < 1 in developmental transcriptomics RNA sequencing data, representing 65% of mapped genes) are indicated.

^§Variants present on the same haplotype in pedigree 18.

^¶Variants present on the same haplotype in pedigree 138.