chr2-178526969-G-A
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2
The NM_001267550.2(TTN):c.*43C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,484,682 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.0053 ( 8 hom., cov: 33)
Exomes 𝑓: 0.00048 ( 11 hom. )
Consequence
TTN
NM_001267550.2 3_prime_UTR
NM_001267550.2 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.40
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 -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
Variant 2-178526969-G-A is Benign according to our data. Variant chr2-178526969-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1214912.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00528 (804/152274) while in subpopulation AFR AF= 0.0182 (758/41552). AF 95% confidence interval is 0.0172. There are 8 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 8 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.*43C>T | 3_prime_UTR_variant | 363/363 | ENST00000589042.5 | NP_001254479.2 | ||
TTN-AS1 | NR_038272.1 | n.219+3333G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.*43C>T | 3_prime_UTR_variant | 363/363 | 5 | NM_001267550.2 | ENSP00000467141 | P1 | ||
TTN-AS1 | ENST00000659121.1 | n.416+3333G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00528 AC: 804AN: 152156Hom.: 8 Cov.: 33
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GnomAD3 exomes AF: 0.00158 AC: 285AN: 179848Hom.: 3 AF XY: 0.00122 AC XY: 118AN XY: 96734
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GnomAD4 exome AF: 0.000483 AC: 643AN: 1332408Hom.: 11 Cov.: 26 AF XY: 0.000423 AC XY: 276AN XY: 651856
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GnomAD4 genome AF: 0.00528 AC: 804AN: 152274Hom.: 8 Cov.: 33 AF XY: 0.00518 AC XY: 386AN XY: 74454
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2018 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at