Proband IDa | Mean BDSIb [%] | Variant | Location of variant residue in human BEST1 3D structure | Possible structural consequences of residue replacement | Relative energy of dimerization ΔΔE cdim [kcal mol−1] | Relative energy of Ca2+ binding ΔΔE dCabin [kcal mol−1] | PMVA predicted pathogenicity of BEST1 variant in logMAR scalee |
---|---|---|---|---|---|---|---|
P1 | 11.90 | p.(Thr2Ile) | At interface to subunit B of cacc Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel formation and stability Channel pore shape Channel activation | − 23 | − 91 | 0.24 |
P2, P3 | 3.55 | p.(Thr4Ile) | At interface to subunits B and E of cacc Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel formation and stability Channel pore shape Channel activation | − 13 | 9 | 0.19 |
P4 | 17.60 | p.(Val9Gly) | At interface to subunit B of cacc Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel formation and stability Channel pore shape Channel activation | − 34 | 62 | 0.29 |
P5–P7 | 7.10 | p.(Gly15Asp) | At interface to subunit B of cacc Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel formation and stability Channel pore shape Channel activation | − 1 | 4 | 0.13 |
P8 | 17.60 | p.(Ser16Phe) | At interface to subunit B of cacc Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel formation and/or pore shape Channel stability Channel activation | 50 | − 19 | 0.37 |
P9 | 15.30 | p.(Arg25Gln) | At interface of cacc to cell membrane Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel embedding in cell membrane Channel pore shape and stability Channel activation | 11 | − 49 | 0.18 |
P10–P12 | 23.10 | p.(Ser27Thr) | At interface to subunit B of cacc Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel formation and stability Channel pore shape Channel activation | − 71 | 16 | 0.47 |
P13 | 0.00 | p.(Tyr29Cys) | At interface to subunit B of cacc Close to K+ binding site of subunit B Close to Ca2+ binding site of subunit B | Channel formation and stability Channel pore shape Channel activation | − 13 | − 3 | 0.19 |
P14 | NA | p.(Arg92Cys) | Lining pore wall of cacc Close to Ca2+ binding site of subunit A At interface to subunit E of cacc | Conformational changes, channel gating Chloride ion throughput or ion selectivity Channel activation Channel stability | 12 | − 23 | 0.19 |
P15 | NA | p.(Trp93Ser) | Close to pore wall of cacc Close to Ca2+ binding site of subunit A At interface to subunit B of cacc | Conformational changes, channel gating Chloride ion throughput or ion selectivity Channel activation Channel stability | 12 | − 15 | 0.19 |
P16 | 9.50 | p.(Pro101Thr) | Lining pore wall of cacc Near interface to subunit B of cacc | Conformational changes, channel gating Chloride ion throughput or ion selectivity Channel stability | − 17 | − 24 | 0.21 |
P17 | 32,60 | p.(Ser108Arg) | At interface to subunit B of cacc | Channel formation and/or pore shape Channel stability | 96 | − 7 | 0.59 |
P18 | 15.30 | p.(Asn179Asp) | At interface to subunits D and E of cacc | Channel formation and/or pore shape Channel stability | 23 | − 50 | 0.24 |
P19 | NA | p.(Trp182Arg) | At interface to subunit E of cacc | Channel formation and/or pore shape Channel stability | 26 | 25 | 0.25 |
P20 | NA | p.(Arg200*) | Cytoplasm side of cacc | Channel gating | – | – | – |
P21–P23 | 7.60 | p.(Arg218Cys) | At interface to subunit E of cacc Near Cl− binding site | Channel stability Channel formation and/or pore shape | − 1 | 25 | 0.13 |
P24 | 23.40 | p.(Arg218Ser) | At interface to subunit E of cacc Near Cl− binding site | Channel stability Channel formation and/or pore shape | 32 | 55 | 0.28 |
P25 | 31.40 | p.(Ile232Asn) | At interface to subunit E of cacc Near pore wall of cacc Close to Ca2+ binding site of subunit A | Channel stability Conformational changes, channel gating Chloride ion throughput or ion selectivity Channel activation | 21 | − 46 | 0.23 |
P26 | 6.50 | p.(Val235Leu) | At interface to subunit E of cacc | Channel formation and stability | 6 | 7 | 0.16 |
P27 | 46.20 | p.(Ala243Thr) | At interface to subunit E of cacc | Channel formation and stability | 5 | − 47 | 0.15 |
P28–P30 | 6.50 | p.(Ala243Val) | At interface to subunit E of cacc | Channel formation and stability | − 7 | − 48 | 0.16 |
P31 | 70.30 | p.(Glu292Gln) | At Ca2+ binding site of subunit A Close to K+ binding site of subunit A At interface to subunit E of cacc | Channel activation Channel stability Channel formation and stability | − 14 | 42 | 0.20 |
P32, P33 | 12,85 | p.(Asn296Lys) | At Ca2+ binding site of subunit A At interface to subunit E of cacc | Channel activation Channel formation and stability | − 17 | 80 | 0.21 |
P34, P35 | NA | p.(Phe298Cys) | Near Ca2+ binding site of subunit A Near interface to subunit E of cacc | Channel activation Channel formation and stability | 26 | − 35 | 0.25 |
P36 | 18.70 | p.(Asp301Glu) | At Ca2+ binding site of subunit A At interface to subunit E of cacc At interface of cacc to cell membrane | Channel activation Channel formation and stability Channel embedding in cell membrane | − 60 | − 7 | 0.42 |