2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAAACAAAACAAA

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):c.26762-29_26762-10dupTTTGTTTTGTTTTGTTTTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 151,004 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 12 hom., cov: 24)

Exomes 𝑓: 0.013 ( 154 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

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 -16 ACMG points.

BP6

Variant 2-178713381-T-TACAAAACAAAACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAAACAAAACAAA is described in ClinVar as [Likely_benign]. Clinvar id is 167797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1575/151004) while in subpopulation NFE AF= 0.0151 (1025/67796). AF 95% confidence interval is 0.0144. There are 12 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.26762-29_26762-10dupTTTGTTTTGTTTTGTTTTGT		intron_variant	Intron 92 of 362	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.26762-10_26762-9insTTTGTTTTGTTTTGTTTTGT		intron_variant	Intron 92 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1576

AN:

150888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00259

Gnomad AMI

AF:

0.0243

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.0116

Gnomad SAS

AF:

0.00127

Gnomad FIN

AF:

0.00849

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0116

GnomAD3 exomes

AF:

0.00890

AC:

894

AN:

100440

Hom.:

AF XY:

0.00900

AC XY:

459

AN XY:

51018

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.00287

Gnomad EAS exome

AF:

0.0130

Gnomad SAS exome

AF:

0.000529

Gnomad FIN exome

AF:

0.00925

Gnomad NFE exome

AF:

0.00901

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0127

AC:

16752

AN:

1317468

Hom.:

154

Cov.:

AF XY:

0.0126

AC XY:

8068

AN XY:

641600

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.00751

Gnomad4 EAS exome

AF:

0.0163

Gnomad4 SAS exome

AF:

0.00114

Gnomad4 FIN exome

AF:

0.0105

Gnomad4 NFE exome

AF:

0.0139

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.0104

AC:

1575

AN:

151004

Hom.:

Cov.:

AF XY:

0.00980

AC XY:

722

AN XY:

73696

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.0117

Gnomad4 SAS

AF:

0.00106

Gnomad4 FIN

AF:

0.00849

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.23030-29_23030-10dup in intron 89 of TTN: This variant is part of a 5 bp repea t (TTTGT) and adds 4 repeat units to 6 present in the reference sequence. It is not expected to have clinical significance because it has been identified in 1.5 % (25/1672) of Finnish chromosomes and 0.7% (59/8302) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s71393436). -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 19, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 04, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:5

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BS1, BS2 -

Sep 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Mar 22, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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