rs768941858
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM5PP2BP4BS2
The NM_001458.5(FLNC):c.7123G>A(p.Val2375Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,910 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2375L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.7123G>A | p.Val2375Ile | missense_variant | 42/48 | ENST00000325888.13 | |
FLNC-AS1 | NR_149055.1 | n.103-1503C>T | intron_variant, non_coding_transcript_variant | ||||
FLNC | NM_001127487.2 | c.7024G>A | p.Val2342Ile | missense_variant | 41/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.7123G>A | p.Val2375Ile | missense_variant | 42/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.7024G>A | p.Val2342Ile | missense_variant | 41/47 | 1 | A1 | ||
FLNC-AS1 | ENST00000469965.1 | n.103-1503C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000401 AC: 10AN: 249434Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135346
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461734Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727172
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2019 | Reported in an adult patient with myofibrillar myopathy (MFM) and lower motor neuron (LMN) syndrome (Chen et al., 2019); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 571045; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31421687) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 10, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2022 | The p.V2375I variant (also known as c.7123G>A), located in coding exon 42 of the FLNC gene, results from a G to A substitution at nucleotide position 7123. The valine at codon 2375 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in an individual with features of myofibrillar myopathy (Chen J et al. BMC Neurol, 2019 Aug;19:198). An alternate amino acid substitution at this codon, p.V2375F, was reported in one individual with hypertrophic cardiomyopathy; however clinical details were limited (Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:[Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, 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 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at