rs1554398369
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2PP2PP3_ModerateBS2
The NM_001458.5(FLNC):āc.1934A>Cā(p.Asp645Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,568 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 (ā ā ). Synonymous variant affecting the same amino acid position (i.e. D645D) 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.1934A>C | p.Asp645Ala | missense_variant | 12/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.1934A>C | p.Asp645Ala | missense_variant | 12/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.1934A>C | p.Asp645Ala | missense_variant | 12/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.1934A>C | p.Asp645Ala | missense_variant | 12/47 | 1 | A1 | ||
FLNC | ENST00000388853.3 | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461568Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727106
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2022 | Reported in a family with left ventricular non-compaction cardiomyopathy in published literature (Kulikova et al. 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Caldern2020[Thesis], Kulikova2021[casereport]) - |
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 16, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 645 of the FLNC protein (p.Asp645Ala). This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 539418). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at