rs189525930
Positions:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2
The NM_001458.5(FLNC):c.1519G>A(p.Gly507Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,614,042 control chromosomes in the GnomAD database, including 1 homozygotes. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00099 ( 1 hom. )
Consequence
FLNC
NM_001458.5 missense
NM_001458.5 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 9.97
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 -8 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, FLNC
BP6
?
Variant 7-128840130-G-A is Benign according to our data. Variant chr7-128840130-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418215.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=4}. Variant chr7-128840130-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000597 (91/152340) while in subpopulation NFE AF= 0.00097 (66/68030). AF 95% confidence interval is 0.000782. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 91 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.1519G>A | p.Gly507Arg | missense_variant | 9/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.1519G>A | p.Gly507Arg | missense_variant | 9/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.1519G>A | p.Gly507Arg | missense_variant | 9/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.1519G>A | p.Gly507Arg | missense_variant | 9/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000598 AC: 91AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000794 AC: 198AN: 249298Hom.: 0 AF XY: 0.000724 AC XY: 98AN XY: 135298
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GnomAD4 exome AF: 0.000987 AC: 1442AN: 1461702Hom.: 1 Cov.: 32 AF XY: 0.000931 AC XY: 677AN XY: 727134
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GnomAD4 genome ? AF: 0.000597 AC: 91AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.000523 AC XY: 39AN XY: 74500
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ExAC
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Asia WGS
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:7
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 23, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 08, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
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 | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | FLNC: PP3, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2019 | Has not been previously published in association with FLNC-related disorders to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 418215; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26555887) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 08, 2022 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2024 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 29, 2021 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2021 | This alteration is classified as 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 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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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