2-178776445-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.5419C>A(p.Pro1807Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,608,876 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1807P) 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.5419C>A | p.Pro1807Thr | missense_variant | 28/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.5419C>A | p.Pro1807Thr | missense_variant | 28/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.5419C>A | p.Pro1807Thr | missense_variant | 28/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.5419C>A | p.Pro1807Thr | missense_variant | 28/46 | 5 | NM_133379.5 | ||
TTN-AS1 | ENST00000659121.1 | n.3872G>T | non_coding_transcript_exon_variant | 12/13 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247770Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134242
GnomAD4 exome AF: 0.0000254 AC: 37AN: 1456756Hom.: 0 Cov.: 33 AF XY: 0.0000207 AC XY: 15AN XY: 724950
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2017 | The P1807T variant in the TTN gene was initially reported as a variant of uncertain significance in a cohort of 870 individuals undergoing whole exome sequencing, and were not selected for cardiac disease (Ng et al., 2013). Subsequently, Sanchez et al. (2016) reported P1807T as a variant of uncertain significance in a 38 year old man with unexplained death who also harbored a second, likely pathogenic variant in a different gene. The P1807T variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, this is a missense variant in a gene in which most reported pathogenic variants associated with cardiomyopathy are truncating/loss-of-function (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at