rs758995789
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_001458.5(FLNC):c.5445C>T(p.Thr1815=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,496 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
FLNC
NM_001458.5 synonymous
NM_001458.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -5.68
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 -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
?
Variant 7-128850849-C-T is Benign according to our data. Variant chr7-128850849-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 539477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128850849-C-T is described in Lovd as [Benign]. Variant chr7-128850849-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-5.68 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000136 (199/1461636) while in subpopulation SAS AF= 0.000707 (61/86258). AF 95% confidence interval is 0.000564. There are 0 homozygotes in gnomad4_exome. There are 107 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.5445C>T | p.Thr1815= | synonymous_variant | 33/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.316-444G>A | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.5346C>T | p.Thr1782= | synonymous_variant | 32/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.5445C>T | p.Thr1815= | synonymous_variant | 33/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.5346C>T | p.Thr1782= | synonymous_variant | 32/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.316-444G>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000922 AC: 14AN: 151860Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000136 AC: 34AN: 249482Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135364
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GnomAD4 exome AF: 0.000136 AC: 199AN: 1461636Hom.: 0 Cov.: 34 AF XY: 0.000147 AC XY: 107AN XY: 727134
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ClinVar
Significance: Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 28, 2021 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2020 | 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 09, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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