rs372172779
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001458.5(FLNC):c.7948G>A(p.Val2650Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,563,640 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2650E) has been classified as Uncertain significance.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.7948G>A | p.Val2650Met | missense_variant | 47/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.102+4350C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.7849G>A | p.Val2617Met | missense_variant | 46/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.7948G>A | p.Val2650Met | missense_variant | 47/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.7849G>A | p.Val2617Met | missense_variant | 46/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.102+4350C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 11AN: 230738Hom.: 0 AF XY: 0.0000556 AC XY: 7AN XY: 125874
GnomAD4 exome AF: 0.0000205 AC: 29AN: 1411412Hom.: 0 Cov.: 25 AF XY: 0.0000184 AC XY: 13AN XY: 705036
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74406
ClinVar
Submissions by phenotype
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 06, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 20, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2022 | The p.V2650M variant (also known as c.7948G>A), located in coding exon 47 of the FLNC gene, results from a G to A substitution at nucleotide position 7948. The valine at codon 2650 is replaced by methionine, an amino acid with highly 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 | Jul 07, 2023 | This variant is present in population databases (rs372172779, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2650 of the FLNC protein (p.Val2650Met). This missense change has been observed in individual(s) with clinical features of FLNC-related conditions (Invitae). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLNC protein function. ClinVar contains an entry for this variant (Variation ID: 575164). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at