2-178745968-C-T

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.11312-4047G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,610,786 control chromosomes in the GnomAD database, including 626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 330 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 296 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0810

Publications

8 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=0.0015295148).

BP6

Variant 2-178745968-C-T is Benign according to our data. Variant chr2-178745968-C-T is described in ClinVar as Benign. ClinVar VariationId is 47802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.11312-4047G>A		intron	N/A	NP_001254479.2
TTN	NM_133379.5		c.16432G>A	p.Val5478Met	missense	Exon 46 of 46	NP_596870.2
TTN	NM_001256850.1		c.10361-4047G>A		intron	N/A	NP_001243779.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.11312-4047G>A	intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.11312-4047G>A	intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.11036-4047G>A	intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0354

AC:

5386

AN:

151938

Hom.:

330

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.0321

GnomAD2 exomes

AF:

0.00888

AC:

2219

AN:

249928

AF XY:

0.00639

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.00464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000310

Gnomad OTH exome

AF:

0.00461

GnomAD4 exome

AF:

0.00358

AC:

5223

AN:

1458730

Hom.:

296

Cov.:

AF XY:

0.00302

AC XY:

2190

AN XY:

725136

show subpopulations

African (AFR)

AF:

0.127

AC:

4249

AN:

33370

American (AMR)

AF:

0.00545

AC:

243

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.000360

AC:

AN:

86104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00522

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000120

AC:

133

AN:

1109622

Other (OTH)

AF:

0.00892

AC:

537

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

279

558

836

1115

1394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.0356

AC:

5413

AN:

152056

Hom.:

330

Cov.:

AF XY:

0.0336

AC XY:

2494

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.124

AC:

5138

AN:

41478

American (AMR)

AF:

0.0114

AC:

174

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000383

AC:

AN:

67944

Other (OTH)

AF:

0.0317

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

242

485

727

970

1212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0169

Hom.:

130

Bravo

AF:

0.0405

ESP6500AA

AF:

0.120

AC:

529

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0113

AC:

1372

Asia WGS

AF:

0.00895

AC:

AN:

3476

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics, Academic 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

Mar 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val5478Met in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 12.3% (460/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs72648915).

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.063

(source)

DANN

Benign

0.34

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

PhyloP100

0.081

PROVEAN

Benign

-0.38

REVEL

Benign

0.028

Sift

Benign

0.39

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.037

ClinPred

0.00043

GERP RS

-6.2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over