rs765438770
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001458.5(FLNC):c.6683G>A(p.Arg2228Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2228W) has been classified as Uncertain significance.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.6683G>A | p.Arg2228Gln | missense_variant | 40/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.103-775C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.6584G>A | p.Arg2195Gln | missense_variant | 39/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.6683G>A | p.Arg2228Gln | missense_variant | 40/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.6584G>A | p.Arg2195Gln | missense_variant | 39/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.103-775C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 243092Hom.: 0 AF XY: 0.00000753 AC XY: 1AN XY: 132772
GnomAD4 exome AF: 0.00000549 AC: 8AN: 1457894Hom.: 0 Cov.: 34 AF XY: 0.00000690 AC XY: 5AN XY: 724992
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function - |
FLNC-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 26, 2022 | The FLNC c.6683G>A variant is predicted to result in the amino acid substitution p.Arg2228Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-128494226-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 05, 2023 | The c.6683G>A (p.R2228Q) alteration is located in exon 40 (coding exon 40) of the FLNC gene. This alteration results from a G to A substitution at nucleotide position 6683, causing the arginine (R) at amino acid position 2228 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at