chr7-128852944-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001458.5(FLNC):c.6121G>T(p.Ala2041Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A2041P) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.6121G>T | p.Ala2041Ser | missense_variant | 37/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.215+341C>A | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.6022G>T | p.Ala2008Ser | missense_variant | 36/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.6121G>T | p.Ala2041Ser | missense_variant | 37/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.6022G>T | p.Ala2008Ser | missense_variant | 36/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.215+341C>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461288Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726952
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
FLNC-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 2023 | The FLNC c.6121G>T variant is predicted to result in the amino acid substitution p.Ala2041Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | Sep 09, 2019 | This sequence change replaces alanine with serine at codon 2041 of the FLNC protein (p.Ala2041Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. 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"). 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at