rs372588069
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_001267550.2(TTN):c.17079C>T(p.Ser5693=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,688 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
TTN
NM_001267550.2 synonymous
NM_001267550.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.07
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 Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
?
Variant 2-178731796-G-A is Benign according to our data. Variant chr2-178731796-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432444.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BP7
?
Synonymous conserved (PhyloP=1.07 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.17079C>T | p.Ser5693= | synonymous_variant | 58/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.17079C>T | p.Ser5693= | synonymous_variant | 58/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.503-2708G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000724 AC: 18AN: 248622Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 134840
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GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461556Hom.: 0 Cov.: 36 AF XY: 0.0000536 AC XY: 39AN XY: 727056
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 16, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2017 | A variant of uncertain significance has been identified in the TTN gene. The c.16128 C>T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 9/16508 (0.05%) alleles from individuals of South Asian ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.16128 C>T variant results in a synonymous change of the residue S5376 in the TTN gene. This nucleotide substitution occurs at a position that is only conserved in mammals. Several in silico splice prediction algorithms predict that this variant creates a weak cryptic splice site in exon 56 upstream of the natural splice donor site for intron 56. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Finally, other truncating TTN variants have been reported in approximately 3% of control alleles and c.16128 C>T is not located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
Cadd
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Dann
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at