rs1183050599
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001458.5(FLNC):c.7834G>A(p.Glu2612Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,562 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. E2612D) has been classified as Uncertain significance.
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 | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.7834G>A | p.Glu2612Lys | missense_variant | 47/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.102+4464C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.7735G>A | p.Glu2579Lys | missense_variant | 46/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.7834G>A | p.Glu2612Lys | missense_variant | 47/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.7735G>A | p.Glu2579Lys | missense_variant | 46/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.102+4464C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 152220Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.0000125 AC: 3AN: 240890Hom.: 0 AF XY: 0.00000761 AC XY: 1AN XY: 131320
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1458562Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2AN XY: 725558
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 16, 2017 | FLNC Glu2612Lys c.7834G>A, exon 47, NM_001458.4, hg19 chr7-128498115-G-A Pathogenic variants in the FLNC gene have been associated with autosomal dominant myofibrillar myopathy and, distal myopathy, and dilated cardiomyopathy. There is preliminary evidence associating the gene with autosomal hypertrophic cardiomyopathy and restrictive cardiomyopathy. Given the lack of case data we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Testing was performed by Invitae. We have seen it in a person with HCM. The variant has not been reported in association with disease in the literature. Per the lab report, "The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine...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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0")." The variant was reported online in 3 of 118,901 individuals (MAF:0.001%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 3 of 16.585 individuals of Latino descent (MAF=0.009%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2023 | The p.E2612K variant (also known as c.7834G>A), located in coding exon 47 of the FLNC gene, results from a G to A substitution at nucleotide position 7834. The glutamic acid at codon 2612 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 472182). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2612 of the FLNC protein (p.Glu2612Lys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at