rs1554398674
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001458.5(FLNC):c.2390-10_2406del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,640 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FLNC
NM_001458.5 splice_acceptor, coding_sequence, intron
NM_001458.5 splice_acceptor, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.613
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.019564686 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3, offset of 24, new splice context is: aggcgtggtgggccctgcAGagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-128842781-CGCTTCTCTGCAGGCGACGTGAGCATCG-C is Pathogenic according to our data. Variant chr7-128842781-CGCTTCTCTGCAGGCGACGTGAGCATCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 478125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.2390-10_2406del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 16/48 | ENST00000325888.13 | ||
FLNC | NM_001127487.2 | c.2390-10_2406del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 16/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.2390-10_2406del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 16/48 | 1 | NM_001458.5 | P3 | ||
FLNC | ENST00000346177.6 | c.2390-10_2406del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 16/47 | 1 | A1 | |||
FLNC | ENST00000388853.3 | n.506-10_522del | splice_acceptor_variant, non_coding_transcript_exon_variant, intron_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460640Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726594
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Deletion of 27 nucleotide bases that spans the canonical splice acceptor site of intron 15 in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016) - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This variant results in the deletion of part of exon 16 (c.2390-10_2406del) of the FLNC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 478125). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at