rs201028676
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001458.5(FLNC):c.6977G>A(p.Arg2326Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,612,576 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 1 hom. )
Consequence
FLNC
NM_001458.5 missense
NM_001458.5 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 5.87
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 -12 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, FLNC
BP4
?
Computational evidence support a benign effect (MetaRNN=0.053786278).
BP6
?
Variant 7-128854662-G-A is Benign according to our data. Variant chr7-128854662-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472154.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000919 (14/152368) while in subpopulation EAS AF= 0.00213 (11/5174). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High AC in GnomAd at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.6977G>A | p.Arg2326Gln | missense_variant | 41/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.103-1265C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.6878G>A | p.Arg2293Gln | missense_variant | 40/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.6977G>A | p.Arg2326Gln | missense_variant | 41/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.6878G>A | p.Arg2293Gln | missense_variant | 40/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.103-1265C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152250Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000284 AC: 7AN: 246076Hom.: 0 AF XY: 0.0000373 AC XY: 5AN XY: 133936
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GnomAD4 exome AF: 0.000116 AC: 169AN: 1460208Hom.: 1 Cov.: 33 AF XY: 0.000113 AC XY: 82AN XY: 726342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2021 | The p.R2326Q variant (also known as c.6977G>A), located in coding exon 41 of the FLNC gene, results from a G to A substitution at nucleotide position 6977. The arginine at codon 2326 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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