rs727503702
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_001267550.2(TTN):c.2084T>C(p.Val695Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 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. V695F) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.2084T>C | p.Val695Ala | missense_variant | 14/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.2084T>C | p.Val695Ala | missense_variant | 14/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.2084T>C | p.Val695Ala | missense_variant | 14/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.2084T>C | p.Val695Ala | missense_variant | 14/46 | 5 | NM_133379.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249134Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134910
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461536Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727046
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 26, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Val695Ala varia nt in TTN has not been reported in individuals with cardiomyopathy and data from large population studies is insufficient to assess the frequency of this varian t. Valine (Val) at position 695 is not conserved in mammals or across evolutiona rily distant species, and several other mammals have an alanine (Ala) at this po sition, suggesting that this change can be tolerated. Computational analyses (bi ochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) s uggest that the Val695Ala variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. Although this data sup ports that the Val695Ala variant may be benign, additional studies are needed to fully assess its clinical significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2018 | The p.V649A variant (also known as c.1946T>C), located in coding exon 12 of the TTN gene, results from a T to C substitution at nucleotide position 1946. The valine at codon 649 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other 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