2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_001267550.2(TTN):c.26762-34_26762-10dupTTTGTTTTGTTTTGTTTTGTTTTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,468,192 control chromosomes in the GnomAD database, including 584 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.014 ( 83 hom., cov: 24)

Exomes 𝑓: 0.010 ( 501 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:7

Conservation

PhyloP100: 1.08

Publications

4 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 -9 ACMG points.

BP6

Variant 2-178713381-T-TACAAAACAAAACAAAACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAAACAAAACAAAACAAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96274.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.26762-34_26762-10dupTTTGTTTTGTTTTGTTTTGTTTTGT		intron_variant	Intron 92 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.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGT		intron_variant	Intron 92 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2151

AN:

150874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00225

Gnomad AMI

AF:

0.00664

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.00929

Gnomad FIN

AF:

0.0368

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00811

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.0229

AC:

2300

AN:

100440

AF XY:

0.0222

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.00839

Gnomad EAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.0312

Gnomad NFE exome

AF:

0.00491

Gnomad OTH exome

AF:

0.0128

GnomAD4 exome

AF:

0.0103

AC:

13514

AN:

1317202

Hom.:

501

Cov.:

AF XY:

0.0101

AC XY:

6497

AN XY:

641532

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

28586

American (AMR)

AF:

0.0113

AC:

249

AN:

22036

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

256

AN:

21164

East Asian (EAS)

AF:

0.146

AC:

4991

AN:

34256

South Asian (SAS)

AF:

0.00540

AC:

337

AN:

62440

European-Finnish (FIN)

AF:

0.0359

AC:

1682

AN:

46836

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

4006

European-Non Finnish (NFE)

AF:

0.00506

AC:

5284

AN:

1043628

Other (OTH)

AF:

0.0121

AC:

655

AN:

54250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

492

984

1477

1969

2461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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:

2145

AN:

150990

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1169

AN XY:

73694

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41026

American (AMR)

AF:

0.0112

AC:

170

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3468

East Asian (EAS)

AF:

0.161

AC:

815

AN:

5048

South Asian (SAS)

AF:

0.00887

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.0368

AC:

385

AN:

10470

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00811

AC:

550

AN:

67796

Other (OTH)

AF:

0.0114

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00523

Hom.:

211

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 23, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 11, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.23030-39_23030-35[11] in intron 89 of TTN: This variant is part of a 5 bp repe at (TTTGT) and adds 5 repeat units to 6 present in the reference sequence. It is not expected to have clinical significance because it has been identified in 13 .5% (73/540) of East Asian chromosomes and 4.2% (70/1672) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org).

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dilated Cardiomyopathy, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Myopathy, myofibrillar, 9, with early respiratory failure

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tibial muscular dystrophy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN-related disorder

Benign:1

Aug 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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