TITINdb

Isoform Positions

Isoform	Protein Position	Transcript Position	Chromosomal Position (HG38)	Chromosomal Position (HG19)
IC	14640	44143;44144;44145	chr2:178631130;178631129;178631128	chr2:179495857;179495856;179495855
N2AB	12999	39220;39221;39222	chr2:178631130;178631129;178631128	chr2:179495857;179495856;179495855
N2A	12072	36439;36440;36441	chr2:178631130;178631129;178631128	chr2:179495857;179495856;179495855
N2B	5575	16948;16949;16950	chr2:178631130;178631129;178631128	chr2:179495857;179495856;179495855
Novex-1	5700	17323;17324;17325	chr2:178631130;178631129;178631128	chr2:179495857;179495856;179495855
Novex-2	5767	17524;17525;17526	chr2:178631130;178631129;178631128	chr2:179495857;179495856;179495855
Novex-3	None	None	chr2:None	chr2:None

Information

• RefSeq wild type amino acid: R
• RefSeq wild type transcript codon: CGC
• RefSeq wild type template codon: GCG
• Domain: Ig-97
• Domain position: 55
• Structural Position: 136
• Q(SASA): 0.124
• 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
R/C	rs72650088	-1.68	1.0	N	0.867	0.296	None	gnomAD-2.1.1	2.82E-05	None	None	None	None	N	None	0	0	None	0	0	None	0	None	0	6.23E-05	0
R/C	rs72650088	-1.68	1.0	N	0.867	0.296	None	gnomAD-3.1.2	1.97E-05	None	None	None	None	N	None	0	0	0	0	0	None	0	0	4.41E-05	0	0
R/C	rs72650088	-1.68	1.0	N	0.867	0.296	None	Begay (2015) Zuo (2021)	None	DCM	comp het with E29590Q	None	None	N	WGS prioritisation; filtering with ANNOVAR; co-segregates within 2-generation family (n = 2, 2 affected (3 total)); significant destabilisation of domain (SM-AFM)	None	None	None	None	None	None	None	None	None	None	None
R/C	rs72650088	-1.68	1.0	N	0.867	0.296	None	gnomAD-4.0.0	2.16969E-05	None	None	None	None	N	None	0	0	None	0	2.23604E-05	None	0	0	2.7128E-05	1.0981E-05	1.60205E-05
R/H	rs752141195	-2.145	1.0	N	0.763	0.373	0.152612264143	gnomAD-2.1.1	1.21E-05	None	None	None	None	N	None	0	0	None	0	0	None	9.81E-05	None	0	0	0
R/H	rs752141195	-2.145	1.0	N	0.763	0.373	0.152612264143	gnomAD-3.1.2	6.58E-06	None	None	None	None	N	None	0	0	0	0	0	None	0	0	1.47E-05	0	0
R/H	rs752141195	-2.145	1.0	N	0.763	0.373	0.152612264143	gnomAD-4.0.0	8.67808E-06	None	None	None	None	N	None	0	1.66756E-05	None	0	2.23654E-05	None	0	0	3.39102E-06	7.68656E-05	1.60149E-05
R/L	None	None	1.0	D	0.773	0.425	0.459818148978	gnomAD-4.0.0	6.84414E-07	None	None	None	None	N	None	0	0	None	0	0	None	0	0	8.99596E-07	0	0
R/P	rs752141195	-1.481	1.0	D	0.86	0.444	0.36453787251	gnomAD-2.1.1	7.15E-06	None	None	None	None	N	None	4.13E-05	0	None	0	0	None	3.27E-05	None	0	0	0
R/P	rs752141195	-1.481	1.0	D	0.86	0.444	0.36453787251	gnomAD-3.1.2	6.58E-06	None	None	None	None	N	None	2.41E-05	0	0	0	0	None	0	0	0	0	0
R/P	rs752141195	-1.481	1.0	D	0.86	0.444	0.36453787251	gnomAD-4.0.0	5.57917E-06	None	None	None	None	N	None	1.33576E-05	0	None	0	0	None	0	0	2.54325E-06	3.2941E-05	3.2041E-05

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
R/A	0.8458	likely_pathogenic	0.8904	pathogenic	-1.521	Destabilizing	0.999	D	0.657	neutral	None	None	None	None	N
R/C	0.313	likely_benign	0.4182	ambiguous	-1.744	Destabilizing	1.0	D	0.867	deleterious	N	0.434341695	None	None	N
R/D	0.9737	likely_pathogenic	0.9802	pathogenic	-1.14	Destabilizing	1.0	D	0.852	deleterious	None	None	None	None	N
R/E	0.8141	likely_pathogenic	0.8577	pathogenic	-0.943	Destabilizing	0.999	D	0.569	neutral	None	None	None	None	N
R/F	0.888	likely_pathogenic	0.9178	pathogenic	-0.932	Destabilizing	1.0	D	0.864	deleterious	None	None	None	None	N
R/G	0.7551	likely_pathogenic	0.8275	pathogenic	-1.847	Destabilizing	1.0	D	0.773	deleterious	D	0.561431065	None	None	N
R/H	0.2311	likely_benign	0.2524	benign	-1.806	Destabilizing	1.0	D	0.763	deleterious	N	0.448603471	None	None	N
R/I	0.6103	likely_pathogenic	0.7424	pathogenic	-0.595	Destabilizing	1.0	D	0.875	deleterious	None	None	None	None	N
R/K	0.3596	ambiguous	0.4003	ambiguous	-1.26	Destabilizing	0.998	D	0.618	neutral	None	None	None	None	N
R/L	0.6361	likely_pathogenic	0.7601	pathogenic	-0.595	Destabilizing	1.0	D	0.773	deleterious	D	0.543151629	None	None	N
R/M	0.6795	likely_pathogenic	0.7832	pathogenic	-1.101	Destabilizing	1.0	D	0.843	deleterious	None	None	None	None	N
R/N	0.9079	likely_pathogenic	0.9173	pathogenic	-1.35	Destabilizing	1.0	D	0.681	prob.neutral	None	None	None	None	N
R/P	0.9847	likely_pathogenic	0.9912	pathogenic	-0.89	Destabilizing	1.0	D	0.86	deleterious	D	0.573891884	None	None	N
R/Q	0.2418	likely_benign	0.2914	benign	-1.144	Destabilizing	1.0	D	0.697	prob.neutral	None	None	None	None	N
R/S	0.9044	likely_pathogenic	0.9257	pathogenic	-2.029	Highly Destabilizing	1.0	D	0.752	deleterious	N	0.428768653	None	None	N
R/T	0.7488	likely_pathogenic	0.8308	pathogenic	-1.631	Destabilizing	1.0	D	0.746	deleterious	None	None	None	None	N
R/V	0.7251	likely_pathogenic	0.8123	pathogenic	-0.89	Destabilizing	1.0	D	0.849	deleterious	None	None	None	None	N
R/W	0.3806	ambiguous	0.474	ambiguous	-0.67	Destabilizing	1.0	D	0.86	deleterious	None	None	None	None	N
R/Y	0.649	likely_pathogenic	0.7134	pathogenic	-0.394	Destabilizing	1.0	D	0.875	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.