rs121909518
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001458.5(FLNC):c.8130G>A(p.Trp2710Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
FLNC
NM_001458.5 stop_gained
NM_001458.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 9.95
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 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-128858475-G-A is Pathogenic according to our data. Variant chr7-128858475-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128858475-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.8130G>A | p.Trp2710Ter | stop_gained | 48/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.102+4050C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.8031G>A | p.Trp2677Ter | stop_gained | 47/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.8130G>A | p.Trp2710Ter | stop_gained | 48/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.8031G>A | p.Trp2677Ter | stop_gained | 47/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.102+4050C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Myofibrillar myopathy 5 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 06, 2023 | _x000D_ Criteria applied: PS3, PP1_STR, PVS1_MOD, PM2_SUP - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2007 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 08, 2019 | - - |
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 23, 2022 | This sequence change creates a premature translational stop signal (p.Trp2710*) in the FLNC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the FLNC protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects FLNC function (PMID: 22961544, 26472074, 26969713). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 18314). This premature translational stop signal has been observed in individual(s) with filaminopathy (PMID: 15929027, 22961544). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at