rs766513255
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2
The NM_001458.5(FLNC):c.4141G>A(p.Gly1381Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,492 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. G1381E) 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.4141G>A | p.Gly1381Arg | missense_variant | 24/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.4141G>A | p.Gly1381Arg | missense_variant | 24/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4141G>A | p.Gly1381Arg | missense_variant | 24/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.4141G>A | p.Gly1381Arg | missense_variant | 24/47 | 1 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248870Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135048
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461262Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726950
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2021 | The p.G1381R variant (also known as c.4141G>A), located in coding exon 24 of the FLNC gene, results from a G to A substitution at nucleotide position 4141. The glycine at codon 1381 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. 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 | May 11, 2020 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FLNC-related disease. This variant is present in population databases (rs766513255, ExAC 0.002%). This sequence change replaces glycine with arginine at codon 1381 of the FLNC protein (p.Gly1381Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at