2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Position:

chr2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_001267550.2(TTN):c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGT variant causes a splice polypyrimidine tract, 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. 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 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.08

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 made for transcript

Verdict is Benign. Variant got -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 id is 96274.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=6}.

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/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2186-366_2186-342dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGTTTTGT		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.503-21116_503-21092dup		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.0229

AC:

2300

AN:

100440

Hom.:

145

AF XY:

0.0222

AC XY:

1131

AN XY:

51018

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 SAS exome

AF:

0.00391

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

Gnomad4 AFR exome

AF:

0.00154

Gnomad4 AMR exome

AF:

0.0113

Gnomad4 ASJ exome

AF:

0.0121

Gnomad4 EAS exome

AF:

0.146

Gnomad4 SAS exome

AF:

0.00540

Gnomad4 FIN exome

AF:

0.0359

Gnomad4 NFE exome

AF:

0.00506

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.0142

AC:

2145

AN:

150990

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1169

AN XY:

73694

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.0112

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.161

Gnomad4 SAS

AF:

0.00887

Gnomad4 FIN

AF:

0.0368

Gnomad4 NFE

AF:

0.00811

Gnomad4 OTH

AF:

0.0114

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2013	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 23, 2015	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2020	- -

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Tibial muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

TTN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over