rs77483833
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_001267550.2(TTN):c.100766-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0019 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0022 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TTN
NM_001267550.2 splice_polypyrimidine_tract, intron
NM_001267550.2 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.001820
2
Clinical Significance
Conservation
PhyloP100: 0.467
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 -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
?
Variant 2-178535858-G-A is Benign according to our data. Variant chr2-178535858-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.100766-9C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000589042.5 | |||
TTN-AS1 | NR_038272.1 | n.316+30G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.100766-9C>T | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_001267550.2 | P1 | |||
TTN-AS1 | ENST00000659121.1 | n.416+12222G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 199AN: 104304Hom.: 0 Cov.: 30 FAILED QC
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GnomAD3 exomes AF: 0.0116 AC: 643AN: 55198Hom.: 0 AF XY: 0.0115 AC XY: 336AN XY: 29178
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00220 AC: 2489AN: 1129796Hom.: 0 Cov.: 27 AF XY: 0.00253 AC XY: 1403AN XY: 553568
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00192 AC: 200AN: 104330Hom.: 0 Cov.: 30 AF XY: 0.00207 AC XY: 103AN XY: 49684
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 22, 2011 | 93062-9C>T in intron 306 of TTN: This variant is not expected to have clinical s ignificance because it is located outside the conserved +/- 1, 2 region of the s plicing consensus sequence and as part of a poly T stretch. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
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 | Invitae | Mar 18, 2022 | - - |
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
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at