chr2-178698916-TAAA-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001267550.2(TTN):c.30683-5_30683-3delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,218,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00083 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01

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: Uncertain_significance. The variant received 0 ACMG points.

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.30683-5_30683-3delTTT	splice_region intron	N/A	NP_001254479.2
TTN	NM_001256850.1		c.29732-5_29732-3delTTT	splice_region intron	N/A	NP_001243779.1
TTN	NM_133378.4		c.26951-5_26951-3delTTT	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.30683-5_30683-3delTTT	splice_region intron	N/A	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.30683-5_30683-3delTTT	splice_region intron	N/A	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.30407-5_30407-3delTTT	splice_region intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

85092

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00410

AC:

270

AN:

65808

AF XY:

0.00408

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.00839

Gnomad ASJ exome

AF:

0.00373

Gnomad EAS exome

AF:

0.00479

Gnomad FIN exome

AF:

0.00453

Gnomad NFE exome

AF:

0.00352

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.000833

AC:

1015

AN:

1218420

Hom.:

AF XY:

0.000887

AC XY:

533

AN XY:

600976

show subpopulations

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

African (AFR)

AF:

0.000815

AC:

AN:

25758

American (AMR)

AF:

0.00330

AC:

AN:

20288

Ashkenazi Jewish (ASJ)

AF:

0.00152

AC:

AN:

21122

East Asian (EAS)

AF:

0.00109

AC:

AN:

32248

South Asian (SAS)

AF:

0.00195

AC:

117

AN:

60068

European-Finnish (FIN)

AF:

0.00168

AC:

AN:

32834

Middle Eastern (MID)

AF:

0.000489

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.000657

AC:

638

AN:

971304

Other (OTH)

AF:

0.000947

AC:

AN:

50704

⚠️ 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: 0.250

Heterozygous variant carriers

147

294

442

589

736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

85092

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

40596

African (AFR)

AF:

0.00

AC:

AN:

21538

American (AMR)

AF:

0.00

AC:

AN:

7934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2106

East Asian (EAS)

AF:

0.00

AC:

AN:

3094

South Asian (SAS)

AF:

0.00

AC:

AN:

2912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

41390

Other (OTH)

AF:

0.00

AC:

AN:

1068

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

Mutation Taster

=71/29

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over