2-178698916-TAAAAAAAAAA-TAAAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001267550.2(TTN):c.30683-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,262,662 control chromosomes in the GnomAD database, including 152 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 125 hom., cov: 30)

Exomes 𝑓: 0.093 ( 27 hom. )

Consequence

TTN
NM_001267550.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

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 -16 ACMG points.

BP6

Variant 2-178698916-T-TA is Benign according to our data. Variant chr2-178698916-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0881 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.30683-3dupT	splice_region intron	N/A	NP_001254479.2
TTN	NM_001256850.1		c.29732-3dupT	splice_region intron	N/A	NP_001243779.1
TTN	NM_133378.4		c.26951-3dupT	splice_region intron	N/A	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.30683-3_30683-2insT	splice_region intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.30683-3_30683-2insT	splice_region intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.30407-3_30407-2insT	splice_region intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0598

AC:

5085

AN:

85034

Hom.:

125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.0115

Gnomad AMR

AF:

0.0568

Gnomad ASJ

AF:

0.0431

Gnomad EAS

AF:

0.00323

Gnomad SAS

AF:

0.00550

Gnomad FIN

AF:

0.0603

Gnomad MID

AF:

0.0329

Gnomad NFE

AF:

0.0905

Gnomad OTH

AF:

0.0646

GnomAD2 exomes

AF:

0.0748

AC:

4922

AN:

65808

AF XY:

0.0724

show subpopulations

Gnomad AFR exome

AF:

0.0702

Gnomad AMR exome

AF:

0.0767

Gnomad ASJ exome

AF:

0.0465

Gnomad EAS exome

AF:

0.0836

Gnomad FIN exome

AF:

0.0478

Gnomad NFE exome

AF:

0.0928

Gnomad OTH exome

AF:

0.0837

GnomAD4 exome

AF:

0.0930

AC:

109555

AN:

1177608

Hom.:

Cov.:

AF XY:

0.0911

AC XY:

52963

AN XY:

581680

show subpopulations

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

African (AFR)

AF:

0.0531

AC:

1324

AN:

24926

American (AMR)

AF:

0.0632

AC:

1276

AN:

20180

Ashkenazi Jewish (ASJ)

AF:

0.0558

AC:

1158

AN:

20760

East Asian (EAS)

AF:

0.0410

AC:

1289

AN:

31460

South Asian (SAS)

AF:

0.0561

AC:

3323

AN:

59248

European-Finnish (FIN)

AF:

0.0650

AC:

2096

AN:

32222

Middle Eastern (MID)

AF:

0.0507

AC:

202

AN:

3984

European-Non Finnish (NFE)

AF:

0.101

AC:

94887

AN:

935602

Other (OTH)

AF:

0.0813

AC:

4000

AN:

49226

⚠️ 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: 0.330

Heterozygous variant carriers

6416

12831

19247

25662

32078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3916

7832

11748

15664

19580

<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:

0.0598

AC:

5084

AN:

85054

Hom.:

125

Cov.:

AF XY:

0.0557

AC XY:

2260

AN XY:

40608

show subpopulations

African (AFR)

AF:

0.0199

AC:

430

AN:

21574

American (AMR)

AF:

0.0567

AC:

450

AN:

7932

Ashkenazi Jewish (ASJ)

AF:

0.0431

AC:

AN:

2110

East Asian (EAS)

AF:

0.00325

AC:

AN:

3078

South Asian (SAS)

AF:

0.00553

AC:

AN:

2894

European-Finnish (FIN)

AF:

0.0603

AC:

264

AN:

4376

Middle Eastern (MID)

AF:

0.0352

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.0905

AC:

3743

AN:

41350

Other (OTH)

AF:

0.0641

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

223

446

669

892

1115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 28, 2016

Eurofins Ntd Llc (ga)

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

Apr 06, 2020

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.26951-3dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.075 in 65808 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 120-fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.26951-3dupT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiomyopathy

Benign:1

May 06, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

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

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

Hypertrophic cardiomyopathy

Benign:1

Feb 07, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.40

Mutation Taster

=99/1

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

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