Isoform Positions
| Isoform | Protein Position | Transcript Position | Chromosomal Position (HG38) | Chromosomal Position (HG19) |
|---|---|---|---|---|
| IC | 35947 | 108064;108065;108066 | chr2:178527149;178527148;178527147 | chr2:179391876;179391875;179391874 |
| N2AB | 34306 | 103141;103142;103143 | chr2:178527149;178527148;178527147 | chr2:179391876;179391875;179391874 |
| N2A | 33379 | 100360;100361;100362 | chr2:178527149;178527148;178527147 | chr2:179391876;179391875;179391874 |
| N2B | 26882 | 80869;80870;80871 | chr2:178527149;178527148;178527147 | chr2:179391876;179391875;179391874 |
| Novex-1 | 27007 | 81244;81245;81246 | chr2:178527149;178527148;178527147 | chr2:179391876;179391875;179391874 |
| Novex-2 | 27074 | 81445;81446;81447 | chr2:178527149;178527148;178527147 | chr2:179391876;179391875;179391874 |
| Novex-3 | None | None | chr2:None | chr2:None |
Information
Reported SAVs
| SNV | RS | DUET |
PolyPhen-2 |
Condel |
Rhapsody |
REVEL |
MVP |
Source |
MAF |
Disease |
Zygosity |
Site annotation |
mCSM PPI |
Predicted PPI site |
Comments |
AFR |
AMR |
AMS |
ASJ |
EAS |
EUR |
FIN |
MDE |
NFE |
SAS |
OTH |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| I/N | None | -1.845 | 0.901 | N | 0.701 | 0.652 | 0.847875809191 | gnomAD-2.1.1 | 4.01E-06 | None | None | None | -0.949(OBSL1) -0.17(OBSCN) | N | None | 0 | 0 | None | 0 | 0 | None | 0 | None | 0 | 8.85E-06 | 0 |
| I/N | None | -1.845 | 0.901 | N | 0.701 | 0.652 | 0.847875809191 | gnomAD-3.1.2 | 1.31E-05 | None | None | None | -0.949(OBSL1) -0.17(OBSCN) | N | None | 0 | 0 | 0 | 0 | 0 | None | 0 | 0 | 2.94E-05 | 0 | 0 |
| I/N | None | -1.845 | 0.901 | N | 0.701 | 0.652 | 0.847875809191 |
Van den Bergh (2003) 
Rudloff (2015)
Evila (2016)
| None |
TMD 
LGMD2J
|
het / comp het with Q22507* | None | -0.949(OBSL1) -0.17(OBSCN) | N | Genetic analysis of TTN in 3-generation BEL family with TMD, incomplete penetrance (n = 6, 5 affected, 1 unaffected carrier (total 9)); Genetic analysis of genes in 10 TMD families; co-segregation in 2-generation family (recessive inheritance, n = 2, 1 affected (total 3; disease state only where compound heterozygous for both I35947N and Q22507*));variant prioritisation; comp het with Q22507*; No significant difference in domain stability; does not affect binding to OBSCN-Ig1; normal expression; monomeric | None | None | None | None | None | None | None | None | None | None | None |
| I/N | None | -1.845 | 0.901 | N | 0.701 | 0.652 | 0.847875809191 | gnomAD-4.0.0 | 1.11535E-05 | None | None | None | -0.949(OBSL1) -0.17(OBSCN) | N | None | 0 | 0 | None | 0 | 0 | None | 0 | 0 | 1.52557E-05 | 0 | 0 |
| I/S | rs281864928 |
None | 0.565 | N | 0.603 | 0.547 | 0.812353797028 | gnomAD-4.0.0 | 6.8414E-07 | None | None | None | -0.756(OBSL1) 0.099(OBSCN) | N | None | 2.98686E-05 | 0 | None | 0 | 0 | None | 0 | 0 | 0 | 0 | 0 |
| I/T | rs281864928 |
-2.31 | 0.008 | D | 0.322 | 0.394 | 0.5936572826 | gnomAD-2.1.1 | 4.01E-06 | None | None | None | -0.901(OBSL1) 0.042(OBSCN) | N | None | 0 | 0 | None | 0 | 0 | None | 0 | None | 0 | 8.85E-06 | 0 |
| I/T | rs281864928 |
-2.31 | 0.008 | D | 0.322 | 0.394 | 0.5936572826 | gnomAD-3.1.2 | 1.31E-05 | None | None | None | -0.901(OBSL1) 0.042(OBSCN) | N | None | 0 | 1.30907E-04 | 0 | 0 | 0 | None | 0 | 0 | 0 | 0 | 0 |
| I/T | rs281864928 |
-2.31 | 0.008 | D | 0.322 | 0.394 | 0.5936572826 | gnomAD-4.0.0 | 3.09819E-06 | None | None | None | -0.901(OBSL1) 0.042(OBSCN) | N | None | 0 | 4.99983E-05 | None | 0 | 0 | None | 0 | 0 | 1.69507E-06 | 0 | 0 |
Saturation Mutagenesis
SAV |
AlphaMissense (IC) |
AlphaMissense Class (IC) |
AlphaMissense (N2AB) |
AlphaMissense Class (N2AB) |
mCSM |
mCSM class |
PolyPhen-2 |
PolyPhen-2 Class |
Rhapsody |
Rhapsody Class |
Condel |
Condel Score |
Site annotation |
mCSM PPI |
Predicted PPI site |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| I/A | 0.4887 | ambiguous | 0.4942 | ambiguous | -2.278 | Highly Destabilizing | 0.415 | N | 0.493 | neutral | None | None | None | -1.054(OBSL1) -0.298(OBSCN) | N |
| I/C | 0.8775 | likely_pathogenic | 0.8936 | pathogenic | -1.506 | Destabilizing | 0.996 | D | 0.631 | neutral | None | None | None | -0.806(OBSL1) 0.169(OBSCN) | N |
| I/D | 0.9482 | likely_pathogenic | 0.9577 | pathogenic | -1.986 | Destabilizing | 0.923 | D | 0.679 | prob.neutral | None | None | None | -0.799(OBSL1) 0.136(OBSCN) | N |
| I/E | 0.8047 | likely_pathogenic | 0.8265 | pathogenic | -1.89 | Destabilizing | 0.923 | D | 0.683 | prob.neutral | None | None | None | -0.951(OBSL1) 0.058(OBSCN) | N |
| I/F | 0.3449 | ambiguous | 0.3379 | benign | -1.495 | Destabilizing | 0.901 | D | 0.533 | neutral | N | 0.488343037 | None | -0.66(OBSL1) 0.292(OBSCN) | N |
| I/G | 0.8956 | likely_pathogenic | 0.9023 | pathogenic | -2.715 | Highly Destabilizing | 0.923 | D | 0.663 | neutral | None | None | None | -0.962(OBSL1) -0.282(OBSCN) | N |
| I/H | 0.8206 | likely_pathogenic | 0.8447 | pathogenic | -1.956 | Destabilizing | 0.996 | D | 0.719 | prob.delet. | None | None | None | -0.667(OBSL1) 0.593(OBSCN) | N |
| I/K | 0.6333 | likely_pathogenic | 0.6678 | pathogenic | -1.67 | Destabilizing | 0.923 | D | 0.684 | prob.neutral | None | None | None | -1.527(OBSL1) -0.123(OBSCN) | N |
| I/L | 0.2037 | likely_benign | 0.199 | benign | -1.081 | Destabilizing | 0.19 | N | 0.35 | neutral | N | 0.511798838 | None | -1.367(OBSL1) -0.363(OBSCN) | N |
| I/M | 0.1501 | likely_benign | 0.1484 | benign | -0.862 | Destabilizing | 0.949 | D | 0.556 | neutral | N | 0.515359218 | None | -1.014(OBSL1) -0.065(OBSCN) | N |
| I/N | 0.7303 | likely_pathogenic | 0.6712 | pathogenic | -1.641 | Destabilizing | 0.901 | D | 0.701 | prob.neutral | N | 0.510196728 | None | -0.949(OBSL1) -0.17(OBSCN) | N |
| I/P | 0.941 | likely_pathogenic | 0.9423 | pathogenic | -1.453 | Destabilizing | 0.961 | D | 0.699 | prob.neutral | None | None | None | -1.257(OBSL1) -0.339(OBSCN) | N |
| I/Q | 0.7015 | likely_pathogenic | 0.7349 | pathogenic | -1.715 | Destabilizing | 0.961 | D | 0.713 | prob.delet. | None | None | None | -0.996(OBSL1) -0.047(OBSCN) | N |
| I/R | 0.5162 | ambiguous | 0.5508 | ambiguous | -1.135 | Destabilizing | 0.923 | D | 0.706 | prob.neutral | None | None | None | -1.7(OBSL1) -0.363(OBSCN) | N |
| I/S | 0.5582 | ambiguous | 0.5864 | pathogenic | -2.346 | Highly Destabilizing | 0.565 | D | 0.603 | neutral | N | 0.519170314 | None | -0.756(OBSL1) 0.099(OBSCN) | N |
| I/T | 0.1873 | likely_benign | 0.1999 | benign | -2.121 | Highly Destabilizing | 0.008 | N | 0.322 | neutral | D | 0.531752822 | None | -0.901(OBSL1) 0.042(OBSCN) | N |
| I/V | 0.0973 | likely_benign | 0.0967 | benign | -1.453 | Destabilizing | 0.003 | N | 0.137 | neutral | N | 0.445648416 | None | -1.257(OBSL1) -0.339(OBSCN) | N |
| I/W | 0.8771 | likely_pathogenic | 0.8884 | pathogenic | -1.687 | Destabilizing | 0.996 | D | 0.736 | prob.delet. | None | None | None | -0.592(OBSL1) 0.34(OBSCN) | N |
| I/Y | 0.7906 | likely_pathogenic | 0.805 | pathogenic | -1.456 | Destabilizing | 0.961 | D | 0.625 | neutral | None | None | None | -0.678(OBSL1) 0.253(OBSCN) | N |
Titin has multiple isoforms, the longest being the theoretical IC (inferred complete) isoform which contains all 363 in-frame titin exons. Here all isoform positions have been mapped onto the IC sequence, with an exception being the C-terminal of the much shorter novex-3 isoform. This contains the out of frame exon 48 which cannot be mapped to the other isoforms.