rs72650053

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):c.36625G>T(p.Val12209Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,588,700 control chromosomes in the GnomAD database, including 1,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V12209V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 57 hom., cov: 29)

Exomes 𝑓: 0.010 ( 1280 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.385

Publications

5 publications found

Variant links:

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 links:

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

TTN-AS1 links:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0014425218).

BP6

Variant 2-178663341-C-A is Benign according to our data. Variant chr2-178663341-C-A is described in ClinVar as Benign. ClinVar VariationId is 192214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.36625G>T	p.Val12209Leu	missense_variant	Exon 173 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.36625G>T	p.Val12209Leu	missense_variant	Exon 173 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2075

AN:

146308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.00347

Gnomad AMR

AF:

0.00514

Gnomad ASJ

AF:

0.0214

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.0404

Gnomad FIN

AF:

0.0241

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00320

Gnomad OTH

AF:

0.0151

GnomAD2 exomes

AF:

0.0234

AC:

5452

AN:

232644

AF XY:

0.0239

show subpopulations

Gnomad AFR exome

AF:

0.0186

Gnomad AMR exome

AF:

0.00453

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.0270

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0103

AC:

14884

AN:

1442274

Hom.:

1280

Cov.:

AF XY:

0.0113

AC XY:

8135

AN XY:

716784

show subpopulations

African (AFR)

AF:

0.0161

AC:

527

AN:

32706

American (AMR)

AF:

0.00417

AC:

175

AN:

41944

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

593

AN:

25740

East Asian (EAS)

AF:

0.141

AC:

5380

AN:

38058

South Asian (SAS)

AF:

0.0418

AC:

3424

AN:

81834

European-Finnish (FIN)

AF:

0.0270

AC:

1431

AN:

52930

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.00211

AC:

2332

AN:

1105440

Other (OTH)

AF:

0.0160

AC:

954

AN:

59536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

535

1070

1606

2141

2676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0142

AC:

2084

AN:

146426

Hom.:

Cov.:

AF XY:

0.0158

AC XY:

1126

AN XY:

71140

show subpopulations

African (AFR)

AF:

0.0167

AC:

658

AN:

39296

American (AMR)

AF:

0.00514

AC:

AN:

14406

Ashkenazi Jewish (ASJ)

AF:

0.0214

AC:

AN:

3410

East Asian (EAS)

AF:

0.130

AC:

607

AN:

4654

South Asian (SAS)

AF:

0.0405

AC:

171

AN:

4224

European-Finnish (FIN)

AF:

0.0241

AC:

245

AN:

10182

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00322

AC:

216

AN:

67094

Other (OTH)

AF:

0.0175

AC:

AN:

2004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.578

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.0134

ESP6500AA

AF:

0.0226

AC:

ESP6500EA

AF:

0.00455

AC:

ExAC

AF:

0.0270

AC:

3229

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28797094) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tibial muscular dystrophy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.0

(source)

DANN

Benign

0.84

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

PhyloP100

-0.39

Vest4

0.058

MPC

0.21

ClinPred

0.0024

GERP RS

2.4

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over