Table 2.

Profiles of candidate variants segregating in the studied patients

Chr	Start	End	dbSNP	Ref	Alt	Gene	Transcript	Exon	Codon change	Amino acid change	Impact	Max_aaf_all (%)	ToMMoaaf (%)	CADD	Cbll
15	41,555,002	41,555,003	–	C	T	CHP1	NM_007236.4	4/7	c.271C > T	p.R91C	missense	–	–	32.0	30.08
6	31,935,498	31,935,499	rs765832592	C	T	SKIV2L	NM_006929.4	22/28	c.2591C > T	p.S864L	missense	0.059	0.050	17.6	44.13
6	32,148,942	32,148,943	–	C	T	AGER	NM_001206929.1.3	11/11	c.1240G > A	p.E414K	missense	–	0.010	12.1	26.89
15	34,048,529	34,048,530	rs766762265	A	G	RYR3	NM_001036.4	59/104	c.8539A > G	p.T2847A	missense	0.307	0.170	9.7	4.68
6	27,368,455	27,368,456	rs749223275	T	G	ZNF391	NM_001076781.2	3/3	c.307 T > G	p.F103V	missense	0.058	0.040	8.7	4.63
15	43,816,412	43,816,413	rs201851388	C	A	MAP1A	NM_002373.5	4/6	c.2742C > A	p.D914E	missense	0.255	0.270	8.0	136.43
6	28,253,358	28,253,359	rs760010326	A	C	PGBD1	NM_001184743.1	3/7	c.428A > C	p.H143P	missense	0.058	0.040	5.1	17.49

Seven segregated candidate variants causing protein alteration and showing a low allele frequency of < 1% and gene expression > 1 median transcripts per kilobase million (TPM) in the cerebellum. Variants are ordered according to the CADD score. None of the other six candidates except for CHP1 mutation demonstrated a causal link to ARCAs. Therefore, we considered that the novel homozygous missense variant CHP1 p.Arg91Cys had been responsible for the ataxic phenotype of the two present cases. Variants were annotated using snpEff 4.3i and gemini 0.19.1. The genomic positions of the variants are based on hg19, and Start and End represent the 0-based and 1-based genomic position, respectively. Impact shows the biological consequence of the most severely affected transcript. Max_aaf_all shows the maximum alternate allele frequency in each population from the 1000 Genomes Project, Exome Sequencing Project, or Exome Aggregation Consortium. ToMMo aaf shows the alternate allele frequency in 3554 Japanese whole genomes obtained from Tohoku University Tohoku Medical Megabank Organization. CADD shows the PHRED-like scaled scores of predictive deleteriousness, and typically scores of 10 or higher indicate possibly pathogenic variants. The column labeled Cbll represents the amount of gene expression in the cerebellum based on GTEx Portal V8. The values show the median TPM