Isoform Positions
| Isoform | Protein Position | Transcript Position | Chromosomal Position (HG38) | Chromosomal Position (HG19) |
|---|---|---|---|---|
| IC | 31732 | 95419;95420;95421 | chr2:178546042;178546041;178546040 | chr2:179410769;179410768;179410767 |
| N2AB | 30091 | 90496;90497;90498 | chr2:178546042;178546041;178546040 | chr2:179410769;179410768;179410767 |
| N2A | 29164 | 87715;87716;87717 | chr2:178546042;178546041;178546040 | chr2:179410769;179410768;179410767 |
| N2B | 22667 | 68224;68225;68226 | chr2:178546042;178546041;178546040 | chr2:179410769;179410768;179410767 |
| Novex-1 | 22792 | 68599;68600;68601 | chr2:178546042;178546041;178546040 | chr2:179410769;179410768;179410767 |
| Novex-2 | 22859 | 68800;68801;68802 | chr2:178546042;178546041;178546040 | chr2:179410769;179410768;179410767 |
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P/L | rs753334568  |
-0.671 | 1.0 | D | 0.888 | 0.727 | 0.908895312635 | gnomAD-2.1.1 | 1.21E-05 | None | None | None | None | N | None | 0 | 0 | None | 0 | 0 | None | 3.27E-05 | None | 0 | 1.78E-05 | 0 |
| P/L | rs753334568 |
-0.671 | 1.0 | D | 0.888 | 0.727 | 0.908895312635 | gnomAD-3.1.2 | 1.31E-05 | None | None | None | None | N | None | 0 | 0 | 0 | 0 | 0 | None | 0 | 0 | 2.94E-05 | 0 | 0 |
| P/L | rs753334568 |
-0.671 | 1.0 | D | 0.888 | 0.727 | 0.908895312635 |
Vasli (2012)
Pfeffer (2013)
Palmio (2013)
Hedberg (2014)
Yue (2015)
Rees (2021)
Sano (2022)
| None |
CM 
HMERF
|
hom / comp het with R34091W | None | None | N | Incomplete penetrance, more severe when homozygous; Found in genetic analysis of TTN in 30 CM patients (homozygous); genetic analysis of genes in 127 undiagnosed patients (likely MFM); WES/WGS prioritisation in 12 HMERF families; genetic analysis in single NMD patient (heterozygous); genetic analysis of CN patient (sporadic) and unaffected carrier (brother); Domain unfolded in vitro (Tm 17 degrees lower than WT) | None | None | None | None | None | None | None | None | None | None | None |
| P/L | rs753334568 |
-0.671 | 1.0 | D | 0.888 | 0.727 | 0.908895312635 | gnomAD-4.0.0 | 9.29582E-06 | None | None | None | None | N | None | 0 | 1.66706E-05 | None | 0 | 0 | None | 0 | 0 | 1.01715E-05 | 1.09786E-05 | 1.60123E-05 |
| P/R | None | None | 1.0 | D | 0.879 | 0.764 | 0.817229753402 | gnomAD-4.0.0 | 6.84245E-07 | None | None | None | None | N | None | 0 | 0 | None | 0 | 0 | None | 0 | 0 | 0 | 1.15937E-05 | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P/A | 0.7955 | likely_pathogenic | 0.8659 | pathogenic | -1.659 | Destabilizing | 1.0 | D | 0.817 | deleterious | D | 0.610153279 | None | None | N |
| P/C | 0.9728 | likely_pathogenic | 0.9841 | pathogenic | -1.159 | Destabilizing | 1.0 | D | 0.843 | deleterious | None | None | None | None | N |
| P/D | 0.998 | likely_pathogenic | 0.9988 | pathogenic | -1.468 | Destabilizing | 1.0 | D | 0.839 | deleterious | None | None | None | None | N |
| P/E | 0.9939 | likely_pathogenic | 0.9959 | pathogenic | -1.447 | Destabilizing | 1.0 | D | 0.839 | deleterious | None | None | None | None | N |
| P/F | 0.9975 | likely_pathogenic | 0.9989 | pathogenic | -1.246 | Destabilizing | 1.0 | D | 0.873 | deleterious | None | None | None | None | N |
| P/G | 0.9815 | likely_pathogenic | 0.9897 | pathogenic | -2.017 | Highly Destabilizing | 1.0 | D | 0.885 | deleterious | None | None | None | None | N |
| P/H | 0.9888 | likely_pathogenic | 0.995 | pathogenic | -1.555 | Destabilizing | 1.0 | D | 0.863 | deleterious | None | None | None | None | N |
| P/I | 0.9768 | likely_pathogenic | 0.9839 | pathogenic | -0.762 | Destabilizing | 1.0 | D | 0.866 | deleterious | None | None | None | None | N |
| P/K | 0.9968 | likely_pathogenic | 0.9981 | pathogenic | -1.404 | Destabilizing | 1.0 | D | 0.836 | deleterious | None | None | None | None | N |
| P/L | 0.9061 | likely_pathogenic | 0.9487 | pathogenic | -0.762 | Destabilizing | 1.0 | D | 0.888 | deleterious | D | 0.658039918 | None | None | N |
| P/M | 0.9885 | likely_pathogenic | 0.9937 | pathogenic | -0.592 | Destabilizing | 1.0 | D | 0.857 | deleterious | None | None | None | None | N |
| P/N | 0.996 | likely_pathogenic | 0.9975 | pathogenic | -1.183 | Destabilizing | 1.0 | D | 0.881 | deleterious | None | None | None | None | N |
| P/Q | 0.9852 | likely_pathogenic | 0.9923 | pathogenic | -1.323 | Destabilizing | 1.0 | D | 0.823 | deleterious | D | 0.659048939 | None | None | N |
| P/R | 0.9881 | likely_pathogenic | 0.9928 | pathogenic | -0.9 | Destabilizing | 1.0 | D | 0.879 | deleterious | D | 0.626576248 | None | None | N |
| P/S | 0.9535 | likely_pathogenic | 0.974 | pathogenic | -1.742 | Destabilizing | 1.0 | D | 0.841 | deleterious | D | 0.579103936 | None | None | N |
| P/T | 0.9458 | likely_pathogenic | 0.9655 | pathogenic | -1.599 | Destabilizing | 1.0 | D | 0.841 | deleterious | D | 0.613373224 | None | None | N |
| P/V | 0.9342 | likely_pathogenic | 0.9515 | pathogenic | -1.027 | Destabilizing | 1.0 | D | 0.896 | deleterious | None | None | None | None | N |
| P/W | 0.9989 | likely_pathogenic | 0.9995 | pathogenic | -1.439 | Destabilizing | 1.0 | D | 0.844 | deleterious | None | None | None | None | N |
| P/Y | 0.9977 | likely_pathogenic | 0.9989 | pathogenic | -1.165 | Destabilizing | 1.0 | D | 0.879 | deleterious | None | None | None | None | 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.