2-178617135-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.47860G>A(p.Ala15954Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000553 in 1,609,216 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). Synonymous variant affecting the same amino acid position (i.e. A15954A) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.47860G>A | p.Ala15954Thr | missense_variant | 255/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.47860G>A | p.Ala15954Thr | missense_variant | 255/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+19454C>T | intron_variant, non_coding_transcript_variant | ||||||
ENST00000605334.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes AF: 0.0000724 AC: 11AN: 151850Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000700 AC: 17AN: 242700Hom.: 0 AF XY: 0.0000683 AC XY: 9AN XY: 131682
GnomAD4 exome AF: 0.0000535 AC: 78AN: 1457366Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 39AN XY: 724696
GnomAD4 genome AF: 0.0000724 AC: 11AN: 151850Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7AN XY: 74138
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 02, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 09, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 05, 2013 | The Ala13386Thr variant in TTN has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 1/8190 European American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity conclusivel y. Additional information is needed to fully assess the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | Variant summary: TTN c.40156G>A (p.Ala13386Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 1602240 control chromosomes (i.e. in 89 carriers) in the gnomAD database, v4.0 dataset. To our knowledge, no occurrence of c.40156G>A in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2019 | The p.A6889T variant (also known as c.20665G>A), located in coding exon 82 of the TTN gene, results from a G to A substitution at nucleotide position 20665. The alanine at codon 6889 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at