7-128847828-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_001458.5(FLNC):c.4420C>T(p.Arg1474Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,442 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 -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4420C>T | p.Arg1474Trp | missense_variant | Exon 25 of 48 | 1 | NM_001458.5 | ENSP00000327145.8 | ||
FLNC | ENST00000346177.6 | c.4420C>T | p.Arg1474Trp | missense_variant | Exon 25 of 47 | 1 | ENSP00000344002.6 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000322 AC: 8AN: 248802Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135070
GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461288Hom.: 0 Cov.: 38 AF XY: 0.0000509 AC XY: 37AN XY: 726948
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
not provided Uncertain:3
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The R1474W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1474W variant is observed in 1/9,826 (0.01%) alleles from individuals of Ashkenazi Jewish background (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -
Cardiomyopathy Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.R1474W variant (also known as c.4420C>T), located in coding exon 25 of the FLNC gene, results from a C to T substitution at nucleotide position 4420. The arginine at codon 1474 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in a hypertrophic cardiomyopathy cohort, but clinical details were limited (Bonaventura J et al. J Am Heart Assoc. 2024 May;13(10):e033565). 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 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at