Table 3

Rare and ultra-rare variants with the CADD score > 30 segregating with the disease in any single family

Position and changeGeneType of variantCADDMAF, %ACMG classification (ACMG criteria met)Family, P(obs)*
chr7:106112481 G/ASYPL1Stop gain41.00Likely pathogenic (PP3, PM2)Y, 0.00278
chr9:38396880 C/TALDH1B1Stop gain40.00.203VUS with pathogenic evidence (PM2, PP3)T, 0.02225
chr18:12702512 G/ACEP76 (PSMG2)Stop gain40.00VUS with pathogenic evidence (PM2, PP3)X, 0.01113
chr12:2855156 C/TTEX52 (ITFG2)Stop gain37.00.166VUS with pathogenic evidence (PM2, PP3)H, 0.01113
chr11:113697354 C/TTMPRSS5Stop gain36.00.031Likely pathogenic (PVS1, PM2)U, 0.00556
chr1:117120939 G/TTRIM45Stop gain36.00.182Benign (BS1, BS2, PVS1)J, 0.02225
chr3:149073278 C/AHLTFStop gain36.00.001VUS with pathogenic evidence (PM2, PP3)I, 0.002781
chr4:81459515 C/TRASGEF1BSplicing35.00.030Pathogenic (PVS1, PM2)J, 0.02225
chr14:96264526 C/TBDKRB1Stop gain35.00.250Benign (BS1, BS2, BP4)I, 0.002781
chr3:53855341 G/AIL17RBMissense35.00.726Benign (BS1, BS2, BP6)A, 0.00556
chr7:2569000 G/AIQCESplicing34.00.024Likely pathogenic (PVS1, PM2)S, 0.01113
chr10:94687805 T/ACYP2C18Stop gain34.00.316Benign (BA1, BP4)J, 0.02225
chr4:88417579 G/THERC6Missense34.00.396Benign (BS1, BS2, BP1, PP3)J, 0.02225
chr17:69026976 C/TABCA9Missense34.00VUS with pathogenic evidence (PM2, PP3)U, 0.00556
chr16:2317763 T/AABCA3Missense33.00.501Benign (BS1, BS2, PP3, PP5)T, 0.02225
chr3:132601106 C/TACKR4 (ACAD11, NPHP3-ACAD11)Stop gain33.00.003Uncertain significance (PM2, BP4)I, 0.002781
chr12:100396328 A/CSLC17A8Splicing33.00Pathogenic (PVS1, PM2)T, 0.02225
chr12:101319592 G/AUTP20Missense32.00Uncertain significance (PM2, PP3, BP1)G, 0.01113
chr12:1885984 G/ACACNA2D4Missense32.00VUS with pathogenic evidence (PM2, PP3)H, 0.01113
chr3:49004877 C/TP4HTMMissense32.00.013Uncertain significance (PM2, BP4)T, 0.02225
chr17:10631666 T/CMYH3Missense32.00.025VUS with pathogenic evidence (PM2, PP3)J, 0.02225
chr15:101324994 G/APCSK6Missense32.00.059Uncertain significance (PM2, BP1)J, 0.02225
chr16:4883689 G/APPLMissense32.00.156Uncertain significance (PM2, PP3, BP1)J, 0.02225
chr17 28385146 T/CSARM1Missense32.00.291VUS with pathogenic evidence (PM2, PP3)G, 0.01113
chr16:89727323 C/TZNF276Missense32.00.969Benign (BS1, BS2, BP6)R, 0.01113
chr12:101677317 G/AMYBPC1Missense32.00.001VUS with pathogenic evidence (PM2, PP3)U, 0.00556
chr12:111803962 G/AALDH2Missense32.00.003Benign (BA1, BP6, BS4, PP3)U, 0.00556
chr12:94279637 G/APLXNC1 (CEP83)Missense32.00Uncertain significance (PM2, PP3, BP1)G, 0.01113
chr12:57244143 G/ASTAC3Missense31.00.024Uncertain significance (PM2)G, 0.01113
chr6:39861001 A/GDAAM2Missense31.00.028Likely pathogenic (PM2, PM1, PP3)H, 0.01113
chr8:99999384 G/ARGS22Missense31.00.046Benign (BA1, BP6, PP3)S, 0.01113
chr21:46114063 G/ACOL6A2Missense31.00.090VUS with pathogenic evidence (PM1, PM2)H, 0.01113
chr2:108499560 A/GGCC2Missense31.00.876Benign (BA1, BP1, PM2, PP3)H, 0.01113
chr3:49652822 G/CBSNMissense31.00VUS with pathogenic evidence (PM2, PP3)D, 0.00139
chr16:80549649 C/GDYNLRB2 (AC105411.1AC108097.1)Missense31.00VUS with pathogenic evidence (PM2, PP3)I, 0.002781
chr7:107916945 T/CDLDMissense30.00VUS with pathogenic evidence (PM2, PP3)J, 0.02225
chr9:37541696 G/AFBXO10 (AL513165.2)Missense30.00VUS 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.