2-178706970-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.29042-16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 1,588,458 control chromosomes in the GnomAD database, including 3,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 498 hom., cov: 33)

Exomes 𝑓: 0.041 ( 2662 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.0280

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:

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 (BayesDel_noAF=-0.8).

BP6

Variant 2-178706970-C-T is Benign according to our data. Variant chr2-178706970-C-T is described in ClinVar as Benign. ClinVar VariationId is 137774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.151 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	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.29042-16G>A	intron	N/A	NP_001254479.2
TTN	NM_001256850.1		c.28091-16G>A	intron	N/A	NP_001243779.1
TTN	NM_133378.4		c.25310-16G>A	intron	N/A	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.29042-16G>A	intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.29042-16G>A	intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.28766-16G>A	intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0625

AC:

9507

AN:

152098

Hom.:

480

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0946

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.0260

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.0575

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0249

Gnomad OTH

AF:

0.0484

GnomAD2 exomes

AF:

0.0748

AC:

15874

AN:

212282

AF XY:

0.0737

show subpopulations

Gnomad AFR exome

AF:

0.0966

Gnomad AMR exome

AF:

0.187

Gnomad ASJ exome

AF:

0.0248

Gnomad EAS exome

AF:

0.0288

Gnomad FIN exome

AF:

0.0565

Gnomad NFE exome

AF:

0.0260

Gnomad OTH exome

AF:

0.0554

GnomAD4 exome

AF:

0.0409

AC:

58715

AN:

1436242

Hom.:

2662

Cov.:

AF XY:

0.0433

AC XY:

30855

AN XY:

712656

show subpopulations

African (AFR)

AF:

0.0955

AC:

3143

AN:

32924

American (AMR)

AF:

0.182

AC:

7439

AN:

40842

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

590

AN:

25580

East Asian (EAS)

AF:

0.0133

AC:

519

AN:

39150

South Asian (SAS)

AF:

0.159

AC:

13102

AN:

82476

European-Finnish (FIN)

AF:

0.0578

AC:

2999

AN:

51900

Middle Eastern (MID)

AF:

0.0360

AC:

206

AN:

5720

European-Non Finnish (NFE)

AF:

0.0254

AC:

27914

AN:

1098188

Other (OTH)

AF:

0.0471

AC:

2803

AN:

59462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

2653

5306

7958

10611

13264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1292

2584

3876

5168

6460

<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:

0.0628

AC:

9561

AN:

152216

Hom.:

498

Cov.:

AF XY:

0.0673

AC XY:

5006

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0955

AC:

3966

AN:

41522

American (AMR)

AF:

0.141

AC:

2162

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

AN:

3472

East Asian (EAS)

AF:

0.0263

AC:

136

AN:

5174

South Asian (SAS)

AF:

0.160

AC:

774

AN:

4824

European-Finnish (FIN)

AF:

0.0575

AC:

609

AN:

10600

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0249

AC:

1691

AN:

68016

Other (OTH)

AF:

0.0479

AC:

101

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

434

868

1303

1737

2171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0406

Hom.:

Bravo

AF:

0.0663

Asia WGS

AF:

0.114

AC:

396

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

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

Mar 04, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 08, 2013

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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 16, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 04, 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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.6

(source)

DANN

Benign

0.38

PhyloP100

0.028

Mutation Taster

=100/0

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