rs201863231
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001458.5(FLNC):c.3133C>A(p.His1045Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,612,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. H1045Q) 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.3133C>A | p.His1045Asn | missense_variant | 20/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.3133C>A | p.His1045Asn | missense_variant | 20/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.3133C>A | p.His1045Asn | missense_variant | 20/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.3133C>A | p.His1045Asn | missense_variant | 20/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000688 AC: 17AN: 247004Hom.: 0 AF XY: 0.0000744 AC XY: 10AN XY: 134334
GnomAD4 exome AF: 0.0000664 AC: 97AN: 1460204Hom.: 0 Cov.: 34 AF XY: 0.0000606 AC XY: 44AN XY: 726138
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2017 | The c.3133 C>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3133 C>A variant is observed in 6/63416 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Multiple in-silico splice prediction models predict that c.3133 C>A creates a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.3133 C>A on splicing in this individual is unknown. If c.3133 C>A does not alter splicing, it will result in the H1045N missense change. The H1045N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with FLNC-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 25, 2021 | - - |
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 12, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 16, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2022 | The p.H1045N variant (also known as c.3133C>A), located in coding exon 20 of the FLNC gene, results from a C to A substitution at nucleotide position 3133. The histidine at codon 1045 is replaced by asparagine, an amino acid with similar properties. This variant has been detected in a cohort in association with personal or family history of dilated cardiomyopathy (DCM) or suspicion of DCM; however, additional detail was limited (Smith E et al. J Am Heart Assoc, 2022 May;11:e024501). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 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