7-128854028-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2PP2BP4_ModerateBS2
The NM_001458.5(FLNC):c.6539G>A(p.Arg2180His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. R2180C) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.6539G>A | p.Arg2180His | missense_variant | 40/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.103-631C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.6440G>A | p.Arg2147His | missense_variant | 39/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.6539G>A | p.Arg2180His | missense_variant | 40/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.6440G>A | p.Arg2147His | missense_variant | 39/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.103-631C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460724Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 726682
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The p.R2180H variant (also known as c.6539G>A), located in coding exon 40 of the FLNC gene, results from a G to A substitution at nucleotide position 6539. The arginine at codon 2180 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a pediatric dilated cardiomyopathy cohort (Khan RS et al. J Am Heart Assoc, 2022 01;11:e022854). This amino acid position is highly 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 | Mar 12, 2019 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FLNC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 2180 of the FLNC protein (p.Arg2180His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at