rs764628080
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_001458.5(FLNC):āc.7319T>Cā(p.Ile2440Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,562 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2440F) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.7319T>C | p.Ile2440Thr | missense_variant | 44/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.103-3188A>G | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.7220T>C | p.Ile2407Thr | missense_variant | 43/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.7319T>C | p.Ile2440Thr | missense_variant | 44/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.7220T>C | p.Ile2407Thr | missense_variant | 43/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.103-3188A>G | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247012Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134310
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460562Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 726706
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 | Dec 03, 2021 | The c.7319T>C (p.I2440T) alteration is located in exon 44 (coding exon 44) of the FLNC gene. This alteration results from a T to C substitution at nucleotide position 7319, causing the isoleucine (I) at amino acid position 2440 to be replaced by a threonine (T). Based on insufficient or conflicting 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 | Invitae | Nov 01, 2022 | This variant has not been reported in the literature in individuals affected with FLNC-related conditions. 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: 539387). This variant is present in population databases (rs764628080, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2440 of the FLNC protein (p.Ile2440Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at