rs12536635
Positions:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001458.5(FLNC):c.1902G>A(p.Glu634=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,614,090 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0040 ( 4 hom., cov: 33)
Exomes 𝑓: 0.0063 ( 43 hom. )
Consequence
FLNC
NM_001458.5 synonymous
NM_001458.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.11
Genes affected
FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
?
Variant 7-128841258-G-A is Benign according to our data. Variant chr7-128841258-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128841258-G-A is described in Lovd as [Benign]. Variant chr7-128841258-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=2.11 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00403 (613/152276) while in subpopulation NFE AF= 0.00684 (465/68000). AF 95% confidence interval is 0.00632. There are 4 homozygotes in gnomad4. There are 264 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 613 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.1902G>A | p.Glu634= | synonymous_variant | 12/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.1902G>A | p.Glu634= | synonymous_variant | 12/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.1902G>A | p.Glu634= | synonymous_variant | 12/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.1902G>A | p.Glu634= | synonymous_variant | 12/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00404 AC: 614AN: 152158Hom.: 4 Cov.: 33
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GnomAD3 exomes AF: 0.00430 AC: 1073AN: 249578Hom.: 2 AF XY: 0.00434 AC XY: 588AN XY: 135374
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GnomAD4 exome AF: 0.00632 AC: 9245AN: 1461814Hom.: 43 Cov.: 33 AF XY: 0.00612 AC XY: 4448AN XY: 727210
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GnomAD4 genome ? AF: 0.00403 AC: 613AN: 152276Hom.: 4 Cov.: 33 AF XY: 0.00355 AC XY: 264AN XY: 74462
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 21, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 19, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 24, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | FLNC: BP4, BS2 - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 16, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 02, 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
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at