rs35813871

Variant names:

• chr2-178785681-G-A
• rs35813871
• NM_001267550.2:c.2432C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.2432C>T​(p.Thr811Ile) variant causes a missense change. The variant allele was found at a frequency of 0.21 in 1,614,008 control chromosomes in the GnomAD database, including 39,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2675 hom., cov: 32)
  • Exomes 𝑓: 0.21 (36931 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 5.94
• Publications: 27 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015586615).
• BP6: Variant 2-178785681-G-A is Benign according to our data. Variant chr2-178785681-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.2432C>T	p.Thr811Ile	missense	Exon 15 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.2432C>T	p.Thr811Ile	missense	Exon 15 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.2432C>T	p.Thr811Ile	missense	Exon 15 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.2432C>T	p.Thr811Ile	missense	Exon 15 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.2432C>T	p.Thr811Ile	missense	Exon 15 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.2156C>T	p.Thr719Ile	missense	Exon 13 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26159 AN: 152086 Hom.: 2676 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.220

GnomAD2 exomes AF: 0.170 AC: 42633 AN: 251288 AF XY: 0.173

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.214 AC: 312429 AN: 1461804 Hom.: 36931 Cov.: 36 AF XY: 0.211 AC XY: 153616 AN XY: 727208

African (AFR) AF: 0.0998 AC: 3342 AN: 33478

American (AMR) AF: 0.124 AC: 5560 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8732 AN: 26136

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39692

South Asian (SAS) AF: 0.0832 AC: 7176 AN: 86258

European-Finnish (FIN) AF: 0.137 AC: 7316 AN: 53412

Middle Eastern (MID) AF: 0.245 AC: 1412 AN: 5766

European-Non Finnish (NFE) AF: 0.239 AC: 266188 AN: 1111946

Other (OTH) AF: 0.210 AC: 12681 AN: 60392

GnomAD4 genome AF: 0.172 AC: 26151 AN: 152204 Hom.: 2675 Cov.: 32 AF XY: 0.165 AC XY: 12292 AN XY: 74408

African (AFR) AF: 0.107 AC: 4452 AN: 41542

American (AMR) AF: 0.170 AC: 2601 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1129 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0730 AC: 352 AN: 4822

European-Finnish (FIN) AF: 0.124 AC: 1313 AN: 10604

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15653 AN: 67974

Other (OTH) AF: 0.218 AC: 459 AN: 2110

Alfa AF: 0.208 Hom.: 8186

Bravo AF: 0.174

TwinsUK AF: 0.247 AC: 915

ALSPAC AF: 0.246 AC: 947

ESP6500AA AF: 0.102 AC: 450

ESP6500EA AF: 0.235 AC: 2017

ExAC AF: 0.169 AC: 20517

Asia WGS AF: 0.0460 AC: 163 AN: 3476

EpiCase AF: 0.253

EpiControl AF: 0.257

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Benign	0.94
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.20
MPC		0.29
ClinPred		0.061	T
GERP RS		5.5
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35813871; hg19: chr2-179650408; COSMIC: COSV60066380; COSMIC: COSV60066380;