rs746478952
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001458.5(FLNC):c.2491G>A(p.Val831Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V831G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001458.5 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 |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.2491G>A | p.Val831Ile | missense_variant | 16/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.2491G>A | p.Val831Ile | missense_variant | 16/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.2491G>A | p.Val831Ile | missense_variant | 16/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.2491G>A | p.Val831Ile | missense_variant | 16/47 | 1 | A1 | ||
FLNC | ENST00000388853.3 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249212Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135334
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461710Hom.: 0 Cov.: 37 AF XY: 0.0000275 AC XY: 20AN XY: 727162
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2021 | The p.V831I variant (also known as c.2491G>A), located in coding exon 16 of the FLNC gene, results from a G to A substitution at nucleotide position 2491. The valine at codon 831 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected in an individual with frontotemporal dementia (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 831 of the FLNC protein (p.Val831Ile). This variant is present in population databases (rs746478952, gnomAD 0.004%). This missense change has been observed in individuals with FLNC-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 539436). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at