rs773579752
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate
The NM_001458.5(FLNC):c.731A>G(p.Asn244Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,994 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N244D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.731A>G | p.Asn244Ser | missense_variant | 4/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.731A>G | p.Asn244Ser | missense_variant | 4/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.731A>G | p.Asn244Ser | missense_variant | 4/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.731A>G | p.Asn244Ser | missense_variant | 4/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249834Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135456
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461848Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6AN XY: 727226
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74324
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2023 | The p.N244S variant (also known as c.731A>G), located in coding exon 4 of the FLNC gene, results from an A to G substitution at nucleotide position 731. The asparagine at codon 244 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. 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. - |
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 | Oct 17, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 244 of the FLNC protein (p.Asn244Ser). This variant is present in population databases (rs773579752, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 571631). 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