rs765230578
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.82583G>A(p.Arg27528Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27528W) has been classified as Uncertain significance.
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.82583G>A | p.Arg27528Gln | missense_variant | 326/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2044-19023C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.82583G>A | p.Arg27528Gln | missense_variant | 326/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-34047C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248854Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135038
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461526Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9AN XY: 727050
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 03, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25589632, 27535533) - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2018 | This sequence change replaces arginine with glutamine at codon 27528 of the TTN protein (p.Arg27528Gln). There is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs765230578, ExAC 0.01%). This variant has not been reported in the literature in individuals with TTN-related disease. This variant is located in the A band of TTN (PMID: 25589632). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2020 | The p.R18463Q variant (also known as c.55388G>A), located in coding exon 153 of the TTN gene, results from a G to A substitution at nucleotide position 55388. The arginine at codon 18463 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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