rs574118437
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001458.5(FLNC):c.3062C>T(p.Ala1021Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1021A) has been classified as Likely benign.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.3062C>T | p.Ala1021Val | missense_variant | 20/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.3062C>T | p.Ala1021Val | missense_variant | 20/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.3062C>T | p.Ala1021Val | missense_variant | 20/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.3062C>T | p.Ala1021Val | missense_variant | 20/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000242 AC: 6AN: 248330Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134980
GnomAD4 exome AF: 0.0000595 AC: 87AN: 1461580Hom.: 0 Cov.: 34 AF XY: 0.0000701 AC XY: 51AN XY: 727120
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152364Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74518
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2020 | The p.A1021V variant (also known as c.3062C>T), located in coding exon 20 of the FLNC gene, results from a C to T substitution at nucleotide position 3062. The alanine at codon 1021 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available 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. - |
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 | Nov 01, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1021 of the FLNC protein (p.Ala1021Val). This variant is present in population databases (rs574118437, gnomAD 0.004%). 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: 472028). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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