2-178698916-TAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001267550.2(TTN):c.30683-12_30683-3dupTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,314,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

TTN
NM_001267550.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.401

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 -8 ACMG points.

BP6

Variant 2-178698916-T-TAAAAAAAAAA is Benign according to our data. Variant chr2-178698916-T-TAAAAAAAAAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 437096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.30683-12_30683-3dupTTTTTTTTTT		splice_region_variant, intron_variant	Intron 111 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.30683-3_30683-2insTTTTTTTTTT		splice_region_variant, intron_variant	Intron 111 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes

AF:

0.0000353

AC:

AN:

84900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00129

AC:

AN:

65808

AF XY:

0.00112

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.000787

Gnomad ASJ exome

AF:

0.000746

Gnomad EAS exome

AF:

0.00571

Gnomad FIN exome

AF:

0.000503

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.000566

GnomAD4 exome

AF:

0.000315

AC:

387

AN:

1229700

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

218

AN XY:

606642

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000691

AC:

AN:

26038

American (AMR)

AF:

0.000973

AC:

AN:

20550

Ashkenazi Jewish (ASJ)

AF:

0.000328

AC:

AN:

21370

East Asian (EAS)

AF:

0.00157

AC:

AN:

32550

South Asian (SAS)

AF:

0.00105

AC:

AN:

60822

European-Finnish (FIN)

AF:

0.000271

AC:

AN:

33190

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.000201

AC:

197

AN:

979868

Other (OTH)

AF:

0.000391

AC:

AN:

51184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.293

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000353

AC:

AN:

84920

Hom.:

Cov.:

AF XY:

0.0000493

AC XY:

AN XY:

40538

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000139

AC:

AN:

21534

American (AMR)

AF:

0.00

AC:

AN:

7944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2110

East Asian (EAS)

AF:

0.00

AC:

AN:

3072

South Asian (SAS)

AF:

0.00

AC:

AN:

2886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

41260

Other (OTH)

AF:

0.00

AC:

AN:

1076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

Sep 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN-related myopathy

Benign:1

Dec 13, 2018

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.40

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over