NM_001267550.2:c.11311+1920G>C

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.11311+1920G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,609,690 control chromosomes in the GnomAD database, including 797,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72577 hom., cov: 32)

Exomes 𝑓: 1.0 ( 725386 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.174

Publications

25 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:

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=8.2521825E-7).

BP6

Variant 2-178751204-C-G is Benign according to our data. Variant chr2-178751204-C-G is described in ClinVar as Benign. ClinVar VariationId is 47735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.11311+1920G>C		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.11311+1920G>C		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes

AF:

0.977

AC:

148363

AN:

151920

Hom.:

72550

Cov.:

show subpopulations

Gnomad AFR

AF:

0.918

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.994

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.981

GnomAD2 exomes

AF:

0.994

AC:

245536

AN:

246976

AF XY:

0.996

show subpopulations

Gnomad AFR exome

AF:

0.920

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.998

AC:

1454075

AN:

1457652

Hom.:

725386

Cov.:

AF XY:

0.998

AC XY:

723135

AN XY:

724640

show subpopulations

African (AFR)

AF:

0.912

AC:

30359

AN:

33294

American (AMR)

AF:

0.996

AC:

44063

AN:

44218

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

25960

AN:

25960

East Asian (EAS)

AF:

1.00

AC:

39570

AN:

39570

South Asian (SAS)

AF:

1.00

AC:

85389

AN:

85414

European-Finnish (FIN)

AF:

1.00

AC:

53248

AN:

53248

Middle Eastern (MID)

AF:

0.996

AC:

5712

AN:

5734

European-Non Finnish (NFE)

AF:

1.00

AC:

1109923

AN:

1110004

Other (OTH)

AF:

0.994

AC:

59851

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

191

382

574

765

956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21658

43316

64974

86632

108290

<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:

0.976

AC:

148446

AN:

152038

Hom.:

72577

Cov.:

AF XY:

0.977

AC XY:

72655

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.917

AC:

38076

AN:

41510

American (AMR)

AF:

0.994

AC:

15149

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5160

AN:

5160

South Asian (SAS)

AF:

1.00

AC:

4814

AN:

4816

European-Finnish (FIN)

AF:

1.00

AC:

10626

AN:

10626

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

67875

AN:

67894

Other (OTH)

AF:

0.981

AC:

2072

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

165

330

496

661

826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.977

Hom.:

54328

Bravo

AF:

0.973

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.920

AC:

4053

ESP6500EA

AF:

0.999

AC:

8585

ExAC

AF:

0.993

AC:

120419

Asia WGS

AF:

0.992

AC:

3451

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.1

(source)

DANN

Benign

0.96

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.40

MetaRNN

Benign

8.3e-7

MetaSVM

Benign

-0.97

PhyloP100

-0.17

PROVEAN

Benign

-0.12

REVEL

Benign

0.14

Sift

Benign

0.10

Sift4G

Benign

0.70

Polyphen

0.0030

Vest4

0.028

MutPred

0.26

Loss of stability (P = 0.0961);

ClinPred

0.0017

GERP RS

3.9

Mutation Taster

=92/8

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

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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