rs1394723230
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001458.5(FLNC):c.7610C>A(p.Ala2537Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A2537T) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.7610C>A | p.Ala2537Asp | missense_variant | 46/48 | ENST00000325888.13 | NP_001449.3 | |
FLNC | NM_001127487.2 | c.7511C>A | p.Ala2504Asp | missense_variant | 45/47 | NP_001120959.1 | ||
FLNC-AS1 | NR_149055.1 | n.103-3769G>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.7610C>A | p.Ala2537Asp | missense_variant | 46/48 | 1 | NM_001458.5 | ENSP00000327145.8 | ||
FLNC | ENST00000346177.6 | c.7511C>A | p.Ala2504Asp | missense_variant | 45/47 | 1 | ENSP00000344002.6 | |||
FLNC-AS1 | ENST00000469965.1 | n.103-3769G>T | intron_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461768Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727188
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2022 | 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; Has not been previously published as pathogenic or benign to our knowledge - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 29, 2024 | The p.A2537D variant (also known as c.7610C>A), located in coding exon 46 of the FLNC gene, results from a C to A substitution at nucleotide position 7610. The alanine at codon 2537 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2017 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FLNC-related disease. This sequence change replaces alanine with aspartic acid at codon 2537 of the FLNC protein (p.Ala2537Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at