rs768103657
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2
The NM_001458.5(FLNC):c.2842G>A(p.Gly948Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G948E) has been classified as Likely benign.
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.2842G>A | p.Gly948Arg | missense_variant | 19/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.2842G>A | p.Gly948Arg | missense_variant | 19/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.2842G>A | p.Gly948Arg | missense_variant | 19/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.2842G>A | p.Gly948Arg | missense_variant | 19/47 | 1 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000333 AC: 8AN: 239986Hom.: 0 AF XY: 0.0000460 AC XY: 6AN XY: 130356
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461536Hom.: 0 Cov.: 34 AF XY: 0.0000523 AC XY: 38AN XY: 727056
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 15, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 29, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 05, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 02, 2023 | The p.G948R variant (also known as c.2842G>A), located in coding exon 19 of the FLNC gene, results from a G to A substitution at nucleotide position 2842. The glycine at codon 948 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in an individual from a cardiomyopathy cohort; however, additional details were not provided (Akinrinade O et al. J Cardiovasc Transl Res. 2023 Jul). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 948 of the FLNC protein (p.Gly948Arg). This variant is present in population databases (rs768103657, gnomAD 0.007%). 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: 472021). 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