rs374132023
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_001458.5(FLNC):c.1757T>C(p.Val586Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,610,582 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.1757T>C | p.Val586Ala | missense_variant | Exon 11 of 48 | 1 | NM_001458.5 | ENSP00000327145.8 | ||
FLNC | ENST00000346177.6 | c.1757T>C | p.Val586Ala | missense_variant | Exon 11 of 47 | 1 | ENSP00000344002.6 |
Frequencies
GnomAD3 genomes AF: 0.000219 AC: 33AN: 150964Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000331 AC: 8AN: 241768Hom.: 0 AF XY: 0.0000303 AC XY: 4AN XY: 131890
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1459618Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 725992
GnomAD4 genome AF: 0.000219 AC: 33AN: 150964Hom.: 0 Cov.: 33 AF XY: 0.000244 AC XY: 18AN XY: 73670
ClinVar
Submissions by phenotype
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Uncertain:1
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not specified Uncertain:1
Variant summary: FLNC c.1757T>C (p.Val586Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 241768 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1757T>C has been reported in the literature in individual(s) affected with Dilated Cardiomyopathy (Begay_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30067491). ClinVar contains an entry for this variant (Variation ID: 471987). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 471987; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Cardiovascular phenotype Uncertain:1
The p.V586A variant (also known as c.1757T>C), located in coding exon 11 of the FLNC gene, results from a T to C substitution at nucleotide position 1757. The valine at codon 586 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Begay RL et al. JACC Clin Electrophysiol, 2018 Apr;4:504-514). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at