rs773119692
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000325888.13(FLNC):c.5668+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,750 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
FLNC
ENST00000325888.13 splice_donor_region, intron
ENST00000325888.13 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00005898
2
Clinical Significance
Conservation
PhyloP100: -0.117
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.5668+6G>A | splice_donor_region_variant, intron_variant | ENST00000325888.13 | NP_001449.3 | |||
FLNC-AS1 | NR_149055.1 | n.315+35C>T | intron_variant, non_coding_transcript_variant | |||||
FLNC | NM_001127487.2 | c.5569+6G>A | splice_donor_region_variant, intron_variant | NP_001120959.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.5668+6G>A | splice_donor_region_variant, intron_variant | 1 | NM_001458.5 | ENSP00000327145 | P3 | |||
FLNC | ENST00000346177.6 | c.5569+6G>A | splice_donor_region_variant, intron_variant | 1 | ENSP00000344002 | A1 | ||||
FLNC-AS1 | ENST00000469965.1 | n.315+35C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249484Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135378
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461750Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727182
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 04, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with FLNC-related disease. This variant is present in population databases (rs773119692, ExAC 0.01%). This sequence change falls in intron 34 of the FLNC gene. It does not directly change the encoded amino acid sequence of the FLNC protein, but it affects a nucleotide within the consensus splice site of the intron. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at