2-178751754-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.11311+1370G>A variant causes a intron change. The variant allele was found at a frequency of 0.000351 in 1,613,094 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 5.01

Publications

3 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074522197).

BP6

Variant 2-178751754-C-T is Benign according to our data. Variant chr2-178751754-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192179.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.11311+1370G>A		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+1370G>A		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

Gnomad ASJ

AF:

0.00924

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000692

AC:

173

AN:

250102

AF XY:

0.000710

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00918

Gnomad EAS exome

AF:

0.000491

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.000821

GnomAD4 exome

AF:

0.000347

AC:

507

AN:

1461070

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

282

AN XY:

726820

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33438

American (AMR)

AF:

0.000179

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00905

AC:

236

AN:

26090

East Asian (EAS)

AF:

0.000303

AC:

AN:

39656

South Asian (SAS)

AF:

0.00128

AC:

110

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000864

AC:

AN:

1111524

Other (OTH)

AF:

0.000712

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000388

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41522

American (AMR)

AF:

0.000459

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00924

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67910

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000551

Hom.:

Bravo

AF:

0.000382

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000328

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

Aug 01, 2014

GeneDx

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: BP4

not specified

Uncertain:1Benign:2

Jul 03, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg3549His variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 46/66562 European chromosomes an d 26/16478 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs148115514). Computational prediction tools and conservation analysis are limited or unavailable for this variant. In summ ary, the clinical significance of the p.Arg3549His variant is uncertain.

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP1;BP6

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.54

M_CAP

Benign

0.011

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.56

PhyloP100

5.0

PROVEAN

Benign

-0.48

REVEL

Benign

0.24

Sift

Benign

0.030

Sift4G

Benign

0.52

Vest4

0.41

ClinPred

0.053

GERP RS

5.0

Mutation Taster

=77/23

polymorphism

(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