rs72646883
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1
The NM_001267550.2(TTN):c.69412+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,607,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )
Consequence
TTN
NM_001267550.2 intron
NM_001267550.2 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.124
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 -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 2-178576913-C-G is Benign according to our data. Variant chr2-178576913-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 47272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178576913-C-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00181 (275/152216) while in subpopulation AFR AF= 0.00599 (249/41564). AF 95% confidence interval is 0.00538. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.69412+10G>C | intron_variant | ENST00000589042.5 | NP_001254479.2 | |||
TTN-AS1 | NR_038272.1 | n.2044-5659C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.69412+10G>C | intron_variant | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.417-20683C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00181 AC: 275AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000458 AC: 112AN: 244464Hom.: 0 AF XY: 0.000392 AC XY: 52AN XY: 132566
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GnomAD4 exome AF: 0.000199 AC: 290AN: 1455724Hom.: 0 Cov.: 35 AF XY: 0.000171 AC XY: 124AN XY: 723798
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GnomAD4 genome AF: 0.00181 AC: 275AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124AN XY: 74406
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | c.61708+10G>C in Intron 273 of TTN: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence an d has been identified in 0.5% (17/3094) of African American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS; dbSNP rs72646883). - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 03, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 19, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
TTN-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 04, 2019 | This variant is classified as likely 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 | Jan 31, 2024 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 11, 2016 | - - |
Early-onset myopathy with fatal cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 10, 2021 | - - |
Computational scores
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Name
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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