2-178679958-CTCTTCT-CTCTTCTTCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_001267550.2(TTN):​c.33513_33515dupAGA​(p.Glu11172dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0162 in 1,613,012 control chromosomes in the GnomAD database, including 231 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 10 hom., cov: 32)
Exomes 𝑓: 0.017 ( 221 hom. )

Consequence

TTN
NM_001267550.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:16

Conservation

PhyloP100: 3.88
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-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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 2-178679958-C-CTCT is Benign according to our data. Variant chr2-178679958-C-CTCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46889.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=12, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1687/152018) while in subpopulation NFE AF= 0.0185 (1258/67912). AF 95% confidence interval is 0.0177. There are 10 homozygotes in gnomad4. There are 750 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.33513_33515dupAGA p.Glu11172dup disruptive_inframe_insertion Exon 140 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.33513_33515dupAGA p.Glu11172dup disruptive_inframe_insertion Exon 140 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.0111
AC:
1687
AN:
151900
Hom.:
10
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00321
Gnomad AMI
AF:
0.00987
Gnomad AMR
AF:
0.00513
Gnomad ASJ
AF:
0.00548
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00497
Gnomad FIN
AF:
0.0141
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0185
Gnomad OTH
AF:
0.00814
GnomAD3 exomes
AF:
0.0113
AC:
2798
AN:
248470
Hom.:
22
AF XY:
0.0115
AC XY:
1554
AN XY:
134786
show subpopulations
Gnomad AFR exome
AF:
0.00356
Gnomad AMR exome
AF:
0.00419
Gnomad ASJ exome
AF:
0.00697
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00533
Gnomad FIN exome
AF:
0.0130
Gnomad NFE exome
AF:
0.0179
Gnomad OTH exome
AF:
0.0111
GnomAD4 exome
AF:
0.0167
AC:
24446
AN:
1460994
Hom.:
221
Cov.:
32
AF XY:
0.0164
AC XY:
11903
AN XY:
726796
show subpopulations
Gnomad4 AFR exome
AF:
0.00272
Gnomad4 AMR exome
AF:
0.00452
Gnomad4 ASJ exome
AF:
0.00590
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00597
Gnomad4 FIN exome
AF:
0.0140
Gnomad4 NFE exome
AF:
0.0198
Gnomad4 OTH exome
AF:
0.0123
GnomAD4 genome
AF:
0.0111
AC:
1687
AN:
152018
Hom.:
10
Cov.:
32
AF XY:
0.0101
AC XY:
750
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00320
Gnomad4 AMR
AF:
0.00512
Gnomad4 ASJ
AF:
0.00548
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00497
Gnomad4 FIN
AF:
0.0141
Gnomad4 NFE
AF:
0.0185
Gnomad4 OTH
AF:
0.00806
Bravo
AF:
0.0101
EpiCase
AF:
0.0164
EpiControl
AF:
0.0176

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:16
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:8
Jun 03, 2024
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 27, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Glu9928dup in exon 137 of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 1.6% (131/7868) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/). -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 26, 2019
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.29781_29783dupAGA (p.Glu9928dup) results in an in-frame duplication in exon 137 of the encoded protein. The variant allele was found at a frequency of 0.011 in 248470 control chromosomes in the gnomAD database, including 22 homozygotes. The observed variant frequency is approximately 18.0 fold of 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 conclusive occurrence of c.29781_29783dupAGA in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic/likely pathogenic variant(s) have been reported in the literature as well as at our laboratory (example DSP c.939+1G>A (Pugh_2014); TTN c.34782_34785delTTGT, p.Cys11595fs*9, our laboratory), providing supporting evidence for a benign role. Four 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. -

Sep 02, 2014
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 06, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 11, 2018
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
Nov 01, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
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

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TTN: PM4:Supporting, BS1, BS2 -

Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
Oct 17, 2013
Blueprint Genetics
Significance: Uncertain significance
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 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiomyopathy Benign:1
May 10, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Feb 28, 2013
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary dilated cardiomyopathy;C1142166:Brugada syndrome Benign:1
Dec 24, 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 v4.3

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.

Other links and lift over

dbSNP: rs368327166; hg19: chr2-179544685; API