TITINdb

Isoform Positions

Isoform	Protein Position	Transcript Position	Chromosomal Position (HG38)	Chromosomal Position (HG19)
IC	18237	54934;54935;54936	chr2:178603978;178603977;178603976	chr2:179468705;179468704;179468703
N2AB	16596	50011;50012;50013	chr2:178603978;178603977;178603976	chr2:179468705;179468704;179468703
N2A	15669	47230;47231;47232	chr2:178603978;178603977;178603976	chr2:179468705;179468704;179468703
N2B	9172	27739;27740;27741	chr2:178603978;178603977;178603976	chr2:179468705;179468704;179468703
Novex-1	9297	28114;28115;28116	chr2:178603978;178603977;178603976	chr2:179468705;179468704;179468703
Novex-2	9364	28315;28316;28317	chr2:178603978;178603977;178603976	chr2:179468705;179468704;179468703
Novex-3	None	None	chr2:None	chr2:None

Information

• RefSeq wild type amino acid: L
• RefSeq wild type transcript codon: CTT
• RefSeq wild type template codon: GAA
• Domain: Fn3-20
• Domain position: 72
• Structural Position: 98
• Q(SASA): 0.596
• Predicted PPI site: N

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
L/P	rs201412693	-0.639	0.013	N	0.341	0.09	None	gnomAD-2.1.1	6.42972E-04	None	None	None	None	N	None	2.06937E-04	6.22242E-04	None	0	0	None	0	None	1.19942E-04	1.12554E-03	8.42933E-04
L/P	rs201412693	-0.639	0.013	N	0.341	0.09	None	gnomAD-3.1.2	6.12076E-04	None	None	None	None	N	None	2.41464E-04	4.59619E-04	0	0	0	None	9.42E-05	0	1.08926E-03	0	4.78469E-04
L/P	rs201412693	-0.639	0.013	N	0.341	0.09	None	1000 genomes	7.98722E-04	None	None	None	None	N	None	0	0	None	None	0	4E-03	None	None	None	0	None
L/P	rs201412693	-0.639	0.013	N	0.341	0.09	None	Rees (2021)	None	CNM	comp het with D32441Ffs*1, W35453*	None	None	N	Genetic analysis of TTN in 30 CM patients; comp het with truncating; Domain unfolded in vitro (Tm 17 degrees lower than WT)	None	None	None	None	None	None	None	None	None	None	None
L/P	rs201412693	-0.639	0.013	N	0.341	0.09	None	gnomAD-4.0.0	9.12083E-04	None	None	None	None	N	None	1.73449E-04	4.83704E-04	None	0	0	None	1.09358E-04	1.65344E-04	1.1746E-03	1.09868E-05	5.60592E-04
L/R	rs201412693	0.001	0.007	N	0.32	0.129	0.554235320232	gnomAD-2.1.1	4.02E-06	None	None	None	None	N	None	0	0	None	0	0	None	0	None	0	8.89E-06	0
L/R	rs201412693	0.001	0.007	N	0.32	0.129	0.554235320232	gnomAD-4.0.0	1.1638E-05	None	None	None	None	N	None	0	0	None	0	0	None	0	0	1.52988E-05	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
L/A	0.1996	likely_benign	0.1805	benign	-1.091	Destabilizing	None	N	0.135	neutral	None	None	None	None	N
L/C	0.6005	likely_pathogenic	0.5753	pathogenic	-0.936	Destabilizing	0.132	N	0.328	neutral	None	None	None	None	N
L/D	0.7394	likely_pathogenic	0.6862	pathogenic	-0.185	Destabilizing	0.004	N	0.379	neutral	None	None	None	None	N
L/E	0.4178	ambiguous	0.3815	ambiguous	-0.191	Destabilizing	0.004	N	0.389	neutral	None	None	None	None	N
L/F	0.215	likely_benign	0.1711	benign	-0.678	Destabilizing	None	N	0.143	neutral	N	0.446293416	None	None	N
L/G	0.5103	ambiguous	0.4483	ambiguous	-1.359	Destabilizing	0.001	N	0.316	neutral	None	None	None	None	N
L/H	0.363	ambiguous	0.288	benign	-0.362	Destabilizing	0.258	N	0.388	neutral	N	0.464532461	None	None	N
L/I	0.0707	likely_benign	0.0677	benign	-0.454	Destabilizing	None	N	0.106	neutral	N	0.361194662	None	None	N
L/K	0.2911	likely_benign	0.2748	benign	-0.627	Destabilizing	0.004	N	0.379	neutral	None	None	None	None	N
L/M	0.1094	likely_benign	0.0996	benign	-0.617	Destabilizing	0.021	N	0.288	neutral	None	None	None	None	N
L/N	0.3244	likely_benign	0.2922	benign	-0.566	Destabilizing	0.009	N	0.351	neutral	None	None	None	None	N
L/P	0.4574	ambiguous	0.3974	ambiguous	-0.634	Destabilizing	0.013	N	0.341	neutral	N	0.459145284	None	None	N
L/Q	0.2081	likely_benign	0.1703	benign	-0.676	Destabilizing	0.018	N	0.411	neutral	None	None	None	None	N
L/R	0.276	likely_benign	0.2232	benign	-0.108	Destabilizing	0.007	N	0.32	neutral	N	0.421797617	None	None	N
L/S	0.2945	likely_benign	0.2515	benign	-1.184	Destabilizing	0.001	N	0.24	neutral	None	None	None	None	N
L/T	0.1489	likely_benign	0.1401	benign	-1.06	Destabilizing	None	N	0.135	neutral	None	None	None	None	N
L/V	0.0959	likely_benign	0.0892	benign	-0.634	Destabilizing	None	N	0.173	neutral	N	0.420298894	None	None	N
L/W	0.4604	ambiguous	0.3363	benign	-0.685	Destabilizing	0.316	N	0.321	neutral	None	None	None	None	N
L/Y	0.4854	ambiguous	0.3918	ambiguous	-0.462	Destabilizing	0.004	N	0.321	neutral	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.