rs10185798
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001267550.2(TTN):c.79689C>A(p.Val26563Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,412 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0076 ( 17 hom., cov: 33)
Exomes 𝑓: 0.00081 ( 8 hom. )
Consequence
TTN
NM_001267550.2 synonymous
NM_001267550.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.09
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 2-178566443-G-T is Benign according to our data. Variant chr2-178566443-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 47379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178566443-G-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.09 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00758 (1154/152186) while in subpopulation AFR AF= 0.0265 (1101/41538). AF 95% confidence interval is 0.0252. There are 17 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 17 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.79689C>A | p.Val26563Val | synonymous_variant | 326/363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.79689C>A | p.Val26563Val | synonymous_variant | 326/363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.00759 AC: 1154AN: 152070Hom.: 17 Cov.: 33
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GnomAD3 exomes AF: 0.00187 AC: 464AN: 248408Hom.: 3 AF XY: 0.00146 AC XY: 197AN XY: 134776
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GnomAD4 exome AF: 0.000808 AC: 1181AN: 1461226Hom.: 8 Cov.: 38 AF XY: 0.000713 AC XY: 518AN XY: 726938
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GnomAD4 genome AF: 0.00758 AC: 1154AN: 152186Hom.: 17 Cov.: 33 AF XY: 0.00734 AC XY: 546AN XY: 74388
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 19, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2012 | Val23995Val in Exon 275 of TTN: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 2.9%(93/3168) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; rs10185798). - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 17, 2024 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
Early-onset myopathy with fatal cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 04, 2021 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Tibial muscular dystrophy Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
Myopathy, myofibrillar, 9, with early respiratory failure Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
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 | Jan 31, 2024 | - - |
Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 03, 2015 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2013 | 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. - |
Computational scores
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Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at