Table 2.
Individualized genotype in postlingually deafened cochlear implantees.
| Subject | Gene | HGVS nucleotide: protein change | REVELa | In silico computational | GERPf | Variant frequencies | Zygosity | Inheritance | MGT | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CADDb | MTc | SIFTd | PP-2e | KRGDBg (1722 individuals) | GMAFh | ||||||||
| SB358–699 | ACTG1 | [NM_001199954.1] c.1013 C > T:p.Ser338Leu | 0.883 | 25.6 | DC | Not predicted | 0.999 (D) | 3.07 | ND | ND | Het | AD | WES |
| SH191–430 | ATP1A3 | [NM_001256214] c.2491 G > A:p.Glu831Lys | 0.967 | 26.5 | DC | 0.0 (D) | 1.0 (D) | 3.88 | ND | ND | Het | de-novo AD | WES |
| SH222–518 | ATP1A3 | [NM_001256214] c.2491 G > A:p.Glu831Lys | 0.967 | 26.5 | DC | 0.0 (D) | 1.0 (D) | 3.88 | ND | ND | Het | de-novo AD | WES |
| SB116–208* | CDH23 | [NM_022124.5] c.719 C > T:p.Pro240Leu | 0.516 | 25.8 | DC | 0.001(D) | 0.704 (PD) | 5.19 | T = 0.001455/5 |
T = 0.00004 (10/249236, GnomAD exome) T = 0.00009 (11/120716, ExAC) T = 0.000 (1/5008, 1000 G) |
Comp het | AR | D130 |
| [NM_022124.5] c.5996 C > G:p.Thr1999Ser | 0.086 | 14.01 | N | Not predicted | 0.0 (B) | 4.14 | G = 0.168899/582 |
G = 0.42292 (104457/246988, GnomAD_exome) G = 0.42914 (51084/119038, ExAC) G = 0.345 (1729/5008, 1000 G) |
|||||
| SH62–147 | CDH23 | [NM_022124.5] c.6604 G > A:p.Asp2202Asn | 0.732 | 18.84 | DC | Not predicted | 1.0 (D) | 5.06 | ND | A = 0.00002 (3/125568, TOPMED) | Comp het | AR | D200 |
| [NM_022124.5] c.5747 G > A:p.Arg1916His | 0.736 | 25 | DC | Not predicted | 1.0 (D) | 4.28 | A = 0.001747/6 |
A = 0.00003 (7/237774, GnomAD_exome) A = 0.00001 (1/125568, TOPMED) A = 0.0001 (4/67492, ExAC) |
|||||
| SB200–388 | COCH | [NM_001135058.1] c.113 G > A:p.Gly38Asp | 0.721 | 27.9 | DC | 0.004 (D) | 0.997 (D) | 5.67 | ND | ND | Het | AD | TES |
| SH14–37 | COCH | [NM_001135058.1] c.113 G > A:p.Gly38Asp | 0.721 | 27.9 | DC | 0.004 (D) | 0.997 (D) | 5.67 | ND | ND | Het | AD | D80 |
| SH185–419 | GJB2 | [NM_004004.5] c.235del:p.Leu79Cysfs*3 | NA | 32 | DC | NA | NA | del = 0.005807/20 |
del = 0.00036 (44/121376, ExAC) del = 0.0005 (15/30968, GnomAD) del = 0.002 (8/5008, 1000 G) |
Comp het | AR | Sanger sequencing | |
| [NM_004004.5] c.578 T > A:p.Val193Glu | 0.868 | 25.5 | DC | 0.002 (D) | 0.979 (D) | 5.65 | ND | ND | |||||
| SH64–149 | ILDR1 | [NM_001199799.1] c.206 C > A: pPro69His | 0.792 | 26.9 | DC | 0.023 (D) | 1.0 (D) | 5.64 | ND |
T = 0.00003 (7/251074, GnomAD_exome) T = 0.00006 (7/125568, TOPMED) T = 0.00004 (5/116010, ExAC) |
Homo | AR | D200 |
| SH53–118 | MYO7A | [NM_000260.3] c.2254 C > T:p.Gln752Ter | NA | 41 | DC | NA | NA | 5.03 | ND | ND | Het | Possibly de-novo AD | D80, D200, WES |
| SB224–437 | MYO15A | [NM_016239.3] c.9790 C > T:p.Gln3264Ter | NA | 51 | DC | NA | NA | 5.61 | ND | ND | Comp het | AR | TES |
| [NM_016239.3] c.10263 C > G:p.Ile3421Met | 0.582 | 23.1 | DC | 0.032 (D) | 0.905 (D) | 2.74 | G = 0.000874/3 |
G = 0.00003 (7/249476, GnomAD_exome) G = 0.00003 (4/120692, ExAC) |
|||||
| SB181–344 | NF2 | [NM_000268.3] c.932_935del: p.Arg311Lysfs*10 | NA | DC | NA | NA | ND | ND | Het | AD | Sanger sequencing | ||
| SH41–90 | NLRP3 | [NM_001243133.1] c.1043 C > T: p.Thr348Met | 0.776 | 28.8 | DC | 0.055 (T) | 0.999 (D) | 3.84 | ND | ND | Het | de-novo AD | D80, D200, WES |
| SB114–206 | SERPINB6 | [NM_001271822.2] c.928del: p.Glu310Serfs*43 | NA | DC | NA | NA | 4.21 | ND | ND | Compound het | AR | WES | |
| [NM_001271822.2] c.772-1 G > A | NA | 31 | DC | NA | NA | 4.67 | ND | T = 0.0000 (1/31404, GnomAD) | |||||
| SH100–214 | SLC26A4 | [NM_000441.2] c.919-2 A > G | NA | 24.8 | DC | NA | NA | 5.62 | G = 0.000873/3 |
G = 0.00036 (90/251010, GnomAD_exome) G = 0.00052 (65/125568, TOPMED) G = 0.00031 (37/121000, ExAC) |
Comp het | AR | Sanger sequencing |
| [NM_000441.2] c.2168 A > G:p.His723Arg | 0.933 | 26.8 | DC | 0.001 (D) | 1.0 (D) | 5.51 | G = 0.005824/20 |
G = 0.00012 (30/251294, GnomAD_exome) G = 0.00006 (8/125568, TOPMED) G = 0.00012 (15/121166, ExAC) G = 0.000 (2/5008, 1000 G) |
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| SH24–53 | SLC26A4 | [NM_000441.2] c.916dup: p.Val306Glyfs*24 | NA | 35 | DC | NA | NA | ND |
dupG = 0.00001 (3/251278, GnomAD_exome) dupG = 0.00002 (2/121236, ExAC) |
Comp het | AR | Sanger sequencing | |
| [NM_000441.2] c.2168 A > G:p.His723Arg | 0.933 | 26.8 | DC | 0.001 (D) | 1.0 (D) | 5.51 | G = 0.005824/20 |
G = 0.00012 (30/251294, GnomAD_exome) G = 0.00006 (8/125568, TOPMED) G = 0.00012 (15/121166, ExAC) G = 0.000 (2/5008, 1000 G) |
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| SB144–238 | TMC1 | [NM_138691.2] c.1714G > A:p.Asp572Asn | 0.465 | 29.7 | DC | 0.122 (T) | 0.999 (D) | 6.16 | ND | ND | Het | AD | D80, WES |
| SB144–239 | TMC1 | [NM_138691.2] c.1714G > A:p.Asp572Asn | 0.465 | 29.7 | DC | 0.122 (T) | 0.999 (D) | 6.16 | ND | ND | Het | AD | D80, WES |
| SB279–550 | TMC1 | [NM_138691.2] c.1714G > A:p.Asp572Asn | 0.465 | 29.7 | DC | 0.122 (T) | 0.999 (D) | 6.16 | ND | ND | Het | AD | WES |
| SH174–387 | TMPRSS3 | [NM_024022.2] c.346 G > A:p.Val116Met | 0.695 | 28.1 | DC | 0.026 (D) | 1.0 (D) | 4.94 | ND |
T = 0.00005 (13/251420, GnomAD_exome) T = 0.00003 (4/125568, TOPMED) T = 0.00006 (7/121402, ExAC) |
Homo | AR | D130 |
| SH51–112 | TMPRSS3 | [NM_024022.2] c.916 G > A:p.Ala306Thr | 0.851 | 34 | DC | 0.002 (D) | 0.999 (D) | 4.8 | T = 0.001164/4 |
T = 0.00014 (36/249060, GnomAD_exome) T = 0.00012 (15/125568, TOPMED) T = 0.00017 (21/121412, ExAC) T = 0.000 (1/5008, 1000 G) |
Comp het | AR | D80, D200, WES |
| [NM_024022.2] c.325 C > T:p.Arg109Trp | 0.767 | 28.4 | DC | 0.0 (D) | 1.0 (D) | 3.99 | A = 0.000588/2 |
A = 0.00013 (33/251350, GnomAD_exome) A = 0.00010 (13/125568, TOPMED) A = 0.00010 (12/121392, ExAC) |
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HGVS, human genome variation society; Homo, homozygosity; Comp Het, compound heterozygosity; Het, heterozygosity; DC, disease causing; D, deleterious; N, neutral; B, benign; NA, not available; ND, not determined; WES: whole exome sequencing; TES: targeted exome sequencing; D80, D130, and D200: Deafness panel comprising 80 genes, 130 genes and 200 genes, respectively.
aRare Exome Variant Ensemble Learner (REVEL; https://sites.google.com/site/revelgenomics/about).
bCombined Annotation Dependent Depletion (CADD; https://cadd.gs.washington.edu/).
cMutation taster (http://www.mutationtaster.org/).
dSorting Intolerant from Tolerant (SIFT; http://sift.jcvi.org/).
ePolyPhen-2 (PP2) prediction score (HumanVar), ranges from 0 to 1 (0 = benign, 1 = probably damaging http://genetics.bwh.harvard.edu/pph2/).
fGenomic Evolutionary Rate Profiling (GERP++; http://genome.ucsc.edu/).
gKorean reference genomic database (KRGDB; http://coda.nih.go.kr/coda/KRGDB/index.jsp).
hGlobal minor allele frequency.
Exome Aggregation Consortium databases (ExAC; http://exac.broadinstitute.org/).
Genome Aggregation Database (GnomAD; https://gnomad.broadinstitute.org/),.
NHLBI Trans-Omics for Precision Medicine (TOPMed; https://bravo.sph.umich.edu/freeze3a/hg19/),.
1000 Genomes Project (1000 G; http://grch37.ensembl.org/Homo_sapiens/Info/Index).
*The causal relationship between CDH23 alteration and Postlingual SNHL in SB116 was previously described (Kim et al.)8.