rs764326184
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001458.5(FLNC):c.6053G>A(p.Arg2018His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,610 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. R2018C) has been classified as Likely benign.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.6053G>A | p.Arg2018His | missense_variant | 37/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.215+409C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.5954G>A | p.Arg1985His | missense_variant | 36/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.6053G>A | p.Arg2018His | missense_variant | 37/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.5954G>A | p.Arg1985His | missense_variant | 36/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.215+409C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249396Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135380
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461460Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20AN XY: 727042
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 05, 2021 | The p.R2018H variant (also known as c.6053G>A), located in coding exon 37 of the FLNC gene, results from a G to A substitution at nucleotide position 6053. The arginine at codon 2018 is replaced by histidine, an amino acid with highly similar properties. In a sudden cardiac death cohort, this variant was reported in a hypertrophic cardiomyopathy case, who had a second FLNC variant also detected (Chanavat V et al. Clin Chim Acta, 2016 Jan;453:80-5). 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 | Jan 17, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2018 of the FLNC protein (p.Arg2018His). This variant is present in population databases (rs764326184, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 26688388). ClinVar contains an entry for this variant (Variation ID: 472124). 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