Table 1. SCN1B variants identified in this study.
Nomenclature | Frequencies | Nucleotide conservation | Prediction of pathogenicity of missense change | Predicted effect on splicing | ||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
A | ESP (NCBI GO)4 mm;mM;MM (tot) | |||||||||||||||||
Variant 1 | Isoform 2 | B | Patient3 | dbSNP | Allelic count and frequency in this study (145 patients) | [avr. read depth] | MAF 1000 Genomes | PhyloP | Pfam | SIFT | Polyphen2 (HumDiv/HumVar) | SNAP | SNPs3D | Panther | MutPred | NetGene | SpliceView | NNSplice |
g.35521779G>T | c.40+15G>T | rs72556351:G>T | G = 232/T = 58 | 0/616 | 0.169 | 0.008 | 0.448 | Nsc | Nc | Nc | ||||||||
c.40+15G>T | G = 0.8/T = 0.2 | [1] | Nsc | Nc | Nc | |||||||||||||
g.35523435C>A | c.44C>A (p.Ser15Tyr) | # 1 | - | C = 289/A = 1 | 0/6503 | n.r.- | 0.992 | 2.142 | Tol | Dam/Ben | Neu | Ben | Not del | Not del | Nsc | Cryptic acceptor lost | Nsc | |
c.44C>A (p.Ser15Tyr) | C = 0.997/A = 0.003 | [77] | Tol | Dam/Dam | Not Neu | Ben | Not del | Nsc | Cryptic acceptor lost | Nsc | ||||||||
g.35524783G>A | c.448+140G>A | # 2 | - | G = 289/A = 1 | 0/3597 | n.r. | 0 | −0.44 | Nsc | Nc | Nc | |||||||
c.588G>A (p.Gly196Gly) | G = 0.997/A = 0.003 | [21] | Nsc | Nc | Nc | |||||||||||||
g.35524824T>C | c.448+181T>C | rs55742440:T>C | T = 162/C = 128 | 660;1645;1213 (3518) | 0.380 | 0 | −0.602 | Nsc | Nc | New acceptor site | ||||||||
c.629T>C (p.Leu210Pro) | T = 0.559/C = 0.441 | [30] | Not tol | Ben/Ben | Not Neu | Not del | Nsc | Nc | New acceptor site | |||||||||
g.35524836G>A | c.448+193G>A | # 3 | rs66876876:G>A | G = 289/A = 1 | 0;23;3455 (3478) | 0.001 | 0 | 0.205 | New acceptor site | New acceptor site | Nc | |||||||
c.641G>A (p.Arg214Gln) | G = 0.997/A = 0.003 | [35] | Tol | Ben/Ben | Not Neu | Not del | New acceptor site | New acceptor site | Nc | |||||||||
g.35524939C>A | c.448+296C>A | rs67701503:C>A | C = 227/A = 63 | 51;728;2546 (3325) | 0.133 | 0.102 | 1.174 | Nc | Cryptic acceptor lost | Nc | ||||||||
c.744C>A (p.Ser248Arg) | C = 0.783/A = 0.217 | [95] | Not tol | Ben/Ben | Not Neu | Not del | Nc | Cryptic acceptor lost | Nc | |||||||||
g.35524944G>C | c.448+301G>C | rs67486287:G>C | G = 228/C = 62 | 47;681;2600 (3328) | 0.129 | 0 | 0.448 | Nc | Cryptic acceptor lost | Nc | ||||||||
c.749G>C (p.Arg250Thr) | G = 0.786/C = 0.214 | [99] | Not tol | Ben/Ben | Not Neu | Not del | Nc | Cryptic acceptor lost | Nc | |||||||||
g.35530073T>C | c.501T>C (p.Ile167Ile) | rs16969930:T>C | T = 280/C = 10 | 3;302;6198 (6503) | 0.014 | 1 | 0.205 | New acceptor site | Nc | Nc | ||||||||
c.*5071T>C | T = 0.966/C = 0.034 | [179] | New acceptor site | Nc | Nc | |||||||||||||
g.35530162C>A | c.590C>A (p.Ala197Asp) | # 4 | - | C = 289/A = 1 | 0/6503 | n.r. | 1 | 1.416 | Not tol | Dam/Ben | Not Neu | Dam | Del | Not del | New donor site | Nsc | Nsc | |
c.*5160C>A | C = 0.997/A = 0.003 | [95] | ||||||||||||||||
g.35530514T>G | c.591-25T>G | rs28365107:T>G | T = 286/G = 4 | 0;143;6360 (6503) | 0.006 | 0 | −0.198 | Nsc | New donor site | Nsc | ||||||||
c.*5512T>G | T = 0.986/G = 0.014 | [78] | ||||||||||||||||
g.35530525C>A | c.591-14C>A | rs28365109:C>A | C = 286/A = 4 | 0;144;6359 (6503) | 0.006 | 0 | 0.044 | Nsc | Nsc | Nsc | ||||||||
c.*5523C>A | C = 0.986/A = 0.014 | [86] | ||||||||||||||||
g.35530580G>A | c.632G>A (p.Cys211Tyr) | # 5 | rs150721582:G>A | G = 289/A = 1 | 0;4;6499 (6503) | 0.001 | 0.992 | 2.869 | Not tol | Dam/Dam | Not Neu | Dam | Del | Not del | New donor site | nc | Nc | |
c.*5578G>A | G = 0.997/A = 0.003 | [79] | ||||||||||||||||
g.35530641G>A | c.*5+31G>A | rs28365108:G>A | G = 288/A = 2 | 1;36;6466 (6503) | 0.001 | 0 | −0.198 | Nsc | nc | Nc | ||||||||
c.*5639G>A | G = 0.993/A = 0.007 | [41] | ||||||||||||||||
g.35530690C>G | c.*6-11C>G | rs28365105:C>G | C = 266/G = 24 | no coverage | 0.037 | 0 | −0.037 | Nsc | Nsc | Nsc | ||||||||
c.*5688C>G | C = 0.917/G = 0.083 | |||||||||||||||||
g.35530737T>C | c.*42T>C | rs2278995:T>C | T = 226/C = 64 | no coverage | 0.148 | 0 | −1.005 | Nsc | nc | Nc | ||||||||
c.*5735T>C | T = 0.779/C = 0.221 | |||||||||||||||||
g.35530771G>T | c.*76G>T | # 6 | - | G = 289/T = 1 | no coverage | n.r. | 0.016 | 0.205 | Nsc | nc | Nc | |||||||
c.*5769G>T | G = 0.997/T = 0.003 | |||||||||||||||||
g.35530781A>C | c.*86A>C | rs2278996:A>C | A = 224/C = 66 | no coverage | 0.146 | 0 | −0.198 | Nc | Nsc | Nc | ||||||||
c.*5779A>C | A = 0.772/C = 0.228 | |||||||||||||||||
g.35530797A>T | c.*102A>T | rs72550274:A>T | A = 288/T = 2 | no coverage | 0.004 | 0 | −1.57 | Nc | Nsc | Nc | ||||||||
c.*5795A>T | A = 0.993/T = 0.007 | |||||||||||||||||
g.35531222T>C | c.*527T>C | rs41275828:T>C | A = 277/C = 13 | no coverage | 0.021 | 0.772 | 0.205 | Nc | Nc | Nc | ||||||||
c.*6220T>C | A = 0.955/C = 0.045 | |||||||||||||||||
g.35531229C>T | c.*534C>T | rs72550266:C>T | C = 289/T = 1 | no coverage | n.r. | 0 | −0.924 | Nc | Nc | Nc | ||||||||
c.*6227C>T | A = 0.997/T = 0.003 |
1Variants are listed according to their genomic position.
2Each variant is described as the expected change on transcript A [NM_001037, NP_001028] (above the line) and transcript B [NM_199037, NP_950238] (under the line) and, when present, the corresponding isoforms.
3Specific patients are referred to only for putatively pathogenic variants. As discussed in the text, pathogenicity predictions are indicated according to the output of each bioinformatic tool: Ben: Benign, Dam: damaging, Del: deleterious, Nc: no changes, Neu: neutral, Not del: not deleterious, Not neu: not neutral, Not tol: Not tolerated, n.r.: not reported, Nsc: no substantial changes, Tol: tolerated.
4Data from the NHLBI GO Exome Sequencing Project (ESP) are reported as: observed genotypes i.e., homozygosis for minor (mm) or Major (MM) allele, and heterozygosis (mM). tot: number of samples sequenced for each position. avr. read depth: the average sample read depth.