7-128848041-A-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PP2PP3_ModerateBP6BS1BS2
The NM_001458.5(FLNC):āc.4553A>Gā(p.Lys1518Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000934 in 1,606,838 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1518Q) 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 -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.4553A>G | p.Lys1518Arg | missense_variant | 26/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.4553A>G | p.Lys1518Arg | missense_variant | 26/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4553A>G | p.Lys1518Arg | missense_variant | 26/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.4553A>G | p.Lys1518Arg | missense_variant | 26/47 | 1 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000545 AC: 83AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000154 AC: 36AN: 233208Hom.: 0 AF XY: 0.000118 AC XY: 15AN XY: 127034
GnomAD4 exome AF: 0.0000461 AC: 67AN: 1454536Hom.: 0 Cov.: 36 AF XY: 0.0000373 AC XY: 27AN XY: 722942
GnomAD4 genome AF: 0.000545 AC: 83AN: 152302Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 27, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2021 | This variant is associated with the following publications: (PMID: 26582918) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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 | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | FLNC NM_001458.4 exon 26 p.Lys1518Arg (c.4553A>G): This variant has not been reported in the literature but is present in 0.1% (44/22636) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-128488095-A-G). This variant is present in ClinVar (Variation ID:195949). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 13, 2022 | - - |
FLNC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 22, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at