Table 4. WES: Nonsense and splice site variants in rare CNV genes in HSCR patients.
| Sample | Chr | Start | Stop | Ref | Alt | Exon | Gene | Type | location | Effect | HGVS cDNA-level | CADD | gnomADv2.1 Exomes | gnomADV2.1 Genomes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SE14-0527 | 17 | 59946466 | 59946466 | T | 23 | INTS2 | insertion | exonic | frameshift | NM_001330417.1:c.3172dupA | 0 | 0 | ||
| HK19-0006 | 17 | 60072727 | 60072727 | C | T | 10 | MED13 | snv | intronic | splicing | NM_005121:c.1968-1G>A | 22.4 | 0 | 0 |
| SE16-3114 | 17 | 59469360 | 59469360 | C | T | 26 | BCAS3 | snv | exonic | stopgain | NM_001320470.1:c.2773C>T | 18.4 | 0.0002 | 0.0007 |
| SE14-0656 | 6 | 31604286 | 31604286 | G | T | 27 | PRRC2A | snv | splicing | splicing | NM_004638.3:c.5836-1G>T | 23.6 | 0.0001 | 3.24E-05 |
| SE16-3123 | 6 | 30692109 | 30692110 | CA | A | 4 | TUBB | substitution | exonic | frameshift | NM_001293212.1:c.1330_1331delCAinsA | . | 0 | 0 |
| SE17-3220 | 7 | 151962296 | 151962296 | T | C | 8 | KMT2C | snv | splicing | splicing | NM_170606.2:c.1013-2A>G | 22 | 8.21E-06 | 0 |
| HK19-0002 | 9 | 28476025 | 28476025 | T | G | LINGO2 | snv | intronic | splicing | NM_001258282:c.-395-2A>C | 23.2 | 0 | 0 | |
| HK19-0003 | 10 | 52103343 | 52103344 | TA | T | 7 | SGMS1 | deletion | exonic | frameshift | NM_147156:c.T529delT-:p.F177del | 33 | 0 | 0 |
| HK19-0004 | 10 | 52104106 | 52104108 | CTG | C | SGMS1 | deletion | intronic | splicing | NM_147156:c.-313-2CAG>—G | 24.5 | 0 | 0 | |
| HK19-0005 | 10 | 52349911 | 52349911 | A | G | SGMS1 | snv | intronic | splicing | NM_147156:c.-683+2T>C | 23 | 0 | 0 | |
| SE16-3109 | 22 | 21065731 | 21065731 | G | A | 51 | PI4KA | snv | exonic | stopgain | NM_058004.3:c.5821C>T | 51 | 0.0002 | 0.0002 |
| HK19-0001 | 3 | 14485130 | 14485130 | A | G | SLC6A6 | snv | intronic | splicing | NM_001134367:c.297-6A>G | 15.92 | 0 | 0 |
Rare putative deleterious nonsense variants and variants predicted to affect splicing in a whole exome sequencing cohort of HSCR (n = 76, 149 controls) [95] and whole genome sequencing cohort of 443 short segment HSCR patients and 493 unaffected controls [46]. Variants in genes intolerant to variation that were also impacted by the de novo 17q23.1—q23.2 loss (INTS2, MED13), the de novo 6p22.1—p21.33 loss (PRRC2A, TUBB), the 9p21 loss (LINGO2), the maternal inherited 10q11.22—q11.23 loss (SGMS1), de novo 7q36.1 gain (KMT2C) and the 3q24 gain (SLC6A6). TUBB is highlighted in gray as this gene is included in the candidate list.