Rare and ultra-rare variants with the CADD score > 30 segregating with the disease in any single family
| Position and change | Gene | Type of variant | CADD | MAF, % | ACMG classification (ACMG criteria met) | Family, P(obs)* |
|---|---|---|---|---|---|---|
| chr7:106112481 G/A | SYPL1 | Stop gain | 41.0 | 0 | Likely pathogenic (PP3, PM2) | Y, 0.00278 |
| chr9:38396880 C/T | ALDH1B1† | Stop gain | 40.0 | 0.203 | VUS with pathogenic evidence (PM2, PP3) | T, 0.02225 |
| chr18:12702512 G/A | CEP76 (PSMG2) | Stop gain | 40.0 | 0 | VUS with pathogenic evidence (PM2, PP3) | X, 0.01113 |
| chr12:2855156 C/T | TEX52 (ITFG2) | Stop gain | 37.0 | 0.166 | VUS with pathogenic evidence (PM2, PP3) | H, 0.01113 |
| chr11:113697354 C/T | TMPRSS5 | Stop gain | 36.0 | 0.031 | Likely pathogenic (PVS1, PM2) | U, 0.00556 |
| chr1:117120939 G/T | TRIM45 | Stop gain | 36.0 | 0.182 | Benign (BS1, BS2, PVS1) | J, 0.02225 |
| chr3:149073278 C/A | HLTF | Stop gain | 36.0 | 0.001 | VUS with pathogenic evidence (PM2, PP3) | I, 0.002781 |
| chr4:81459515 C/T | RASGEF1B | Splicing | 35.0 | 0.030 | Pathogenic (PVS1, PM2) | J, 0.02225 |
| chr14:96264526 C/T | BDKRB1 | Stop gain | 35.0 | 0.250 | Benign (BS1, BS2, BP4) | I, 0.002781 |
| chr3:53855341 G/A | IL17RB | Missense | 35.0 | 0.726 | Benign (BS1, BS2, BP6) | A, 0.00556 |
| chr7:2569000 G/A | IQCE | Splicing | 34.0 | 0.024 | Likely pathogenic (PVS1, PM2) | S, 0.01113 |
| chr10:94687805 T/A | CYP2C18 | Stop gain | 34.0 | 0.316 | Benign (BA1, BP4) | J, 0.02225 |
| chr4:88417579 G/T | HERC6 | Missense | 34.0 | 0.396 | Benign (BS1, BS2, BP1, PP3) | J, 0.02225 |
| chr17:69026976 C/T | ABCA9 | Missense | 34.0 | 0 | VUS with pathogenic evidence (PM2, PP3) | U, 0.00556 |
| chr16:2317763 T/A | ABCA3 | Missense | 33.0 | 0.501 | Benign (BS1, BS2, PP3, PP5) | T, 0.02225 |
| chr3:132601106 C/T | ACKR4 (ACAD11, NPHP3-ACAD11) | Stop gain | 33.0 | 0.003 | Uncertain significance (PM2, BP4) | I, 0.002781 |
| chr12:100396328 A/C | SLC17A8‡ | Splicing | 33.0 | 0 | Pathogenic (PVS1, PM2) | T, 0.02225 |
| chr12:101319592 G/A | UTP20 | Missense | 32.0 | 0 | Uncertain significance (PM2, PP3, BP1) | G, 0.01113 |
| chr12:1885984 G/A | CACNA2D4 | Missense | 32.0 | 0 | VUS with pathogenic evidence (PM2, PP3) | H, 0.01113 |
| chr3:49004877 C/T | P4HTM | Missense | 32.0 | 0.013 | Uncertain significance (PM2, BP4) | T, 0.02225 |
| chr17:10631666 T/C | MYH3 | Missense | 32.0 | 0.025 | VUS with pathogenic evidence (PM2, PP3) | J, 0.02225 |
| chr15:101324994 G/A | PCSK6 | Missense | 32.0 | 0.059 | Uncertain significance (PM2, BP1) | J, 0.02225 |
| chr16:4883689 G/A | PPL | Missense | 32.0 | 0.156 | Uncertain significance (PM2, PP3, BP1) | J, 0.02225 |
| chr17 28385146 T/C | SARM1 | Missense | 32.0 | 0.291 | VUS with pathogenic evidence (PM2, PP3) | G, 0.01113 |
| chr16:89727323 C/T | ZNF276 | Missense | 32.0 | 0.969 | Benign (BS1, BS2, BP6) | R, 0.01113 |
| chr12:101677317 G/A | MYBPC1 | Missense | 32.0 | 0.001 | VUS with pathogenic evidence (PM2, PP3) | U, 0.00556 |
| chr12:111803962 G/A | ALDH2† | Missense | 32.0 | 0.003 | Benign (BA1, BP6, BS4, PP3) | U, 0.00556 |
| chr12:94279637 G/A | PLXNC1 (CEP83) | Missense | 32.0 | 0 | Uncertain significance (PM2, PP3, BP1) | G, 0.01113 |
| chr12:57244143 G/A | STAC3 | Missense | 31.0 | 0.024 | Uncertain significance (PM2) | G, 0.01113 |
| chr6:39861001 A/G | DAAM2 | Missense | 31.0 | 0.028 | Likely pathogenic (PM2, PM1, PP3) | H, 0.01113 |
| chr8:99999384 G/A | RGS22 | Missense | 31.0 | 0.046 | Benign (BA1, BP6, PP3) | S, 0.01113 |
| chr21:46114063 G/A | COL6A2 | Missense | 31.0 | 0.090 | VUS with pathogenic evidence (PM1, PM2) | H, 0.01113 |
| chr2:108499560 A/G | GCC2 | Missense | 31.0 | 0.876 | Benign (BA1, BP1, PM2, PP3) | H, 0.01113 |
| chr3:49652822 G/C | BSN‡ | Missense | 31.0 | 0 | VUS with pathogenic evidence (PM2, PP3) | D, 0.00139 |
| chr16:80549649 C/G | DYNLRB2 (AC105411.1AC108097.1) | Missense | 31.0 | 0 | VUS with pathogenic evidence (PM2, PP3) | I, 0.002781 |
| chr7:107916945 T/C | DLD† | Missense | 30.0 | 0 | VUS with pathogenic evidence (PM2, PP3) | J, 0.02225 |
| chr9:37541696 G/A | FBXO10 (AL513165.2) | Missense | 30.0 | 0 | VUS with pathogenic evidence (PM2, PP3) | T, 0.02225 |
ACMG = American College of Medical Genetics and Genomics; CADD = combined annotation dependent depletion; MAF = minor allele frequency; VUS = variant of unknown significance.
↵* P(obs) = probability of cosegregation of a rare variant with a CADD > 30 in a given family, Bonferroni corrected to 17 families: P(obs) = P(seg) × (P(var) × 17. P(var) = 1 – Πn1 (1 – MAFn) n = 67 – overall number of variants with CADD > 30.
↵† Genes encoding dehydrogenases influencing oxidoreductase activity.
↵‡ Genes involved in sensory processing of sound by hair cells of the cochlea.