rs374132023

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_001458.5(FLNC):​c.1757T>C​(p.Val586Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,610,582 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).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

2
11
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 6.27
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.32348818).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000219 (33/150964) while in subpopulation AFR AF= 0.000758 (31/40888). AF 95% confidence interval is 0.000549. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.1757T>C p.Val586Ala missense_variant Exon 11 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.1757T>C p.Val586Ala missense_variant Exon 11 of 47 NP_001120959.1 Q14315-2Q59H94

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.1757T>C p.Val586Ala missense_variant Exon 11 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1
FLNCENST00000346177.6 linkc.1757T>C p.Val586Ala missense_variant Exon 11 of 47 1 ENSP00000344002.6 Q14315-2

Frequencies

GnomAD3 genomes
AF:
0.000219
AC:
33
AN:
150964
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000758
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000658
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000485
GnomAD3 exomes
AF:
0.0000331
AC:
8
AN:
241768
Hom.:
0
AF XY:
0.0000303
AC XY:
4
AN XY:
131890
show subpopulations
Gnomad AFR exome
AF:
0.000407
Gnomad AMR exome
AF:
0.0000294
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1459618
Hom.:
0
Cov.:
34
AF XY:
0.0000165
AC XY:
12
AN XY:
725992
show subpopulations
Gnomad4 AFR exome
AF:
0.000718
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000830
GnomAD4 genome
AF:
0.000219
AC:
33
AN:
150964
Hom.:
0
Cov.:
33
AF XY:
0.000244
AC XY:
18
AN XY:
73670
show subpopulations
Gnomad4 AFR
AF:
0.000758
Gnomad4 AMR
AF:
0.0000658
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000485
Alfa
AF:
0.000133
Hom.:
0
Bravo
AF:
0.000219
ESP6500AA
AF:
0.000500
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Uncertain:1
Sep 29, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Dec 24, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FLNC c.1757T>C (p.Val586Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 241768 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1757T>C has been reported in the literature in individual(s) affected with Dilated Cardiomyopathy (Begay_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30067491). ClinVar contains an entry for this variant (Variation ID: 471987). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
Sep 09, 2021
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 471987; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Cardiovascular phenotype Uncertain:1
Dec 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.V586A variant (also known as c.1757T>C), located in coding exon 11 of the FLNC gene, results from a T to C substitution at nucleotide position 1757. The valine at codon 586 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Begay RL et al. JACC Clin Electrophysiol, 2018 Apr;4:504-514). 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
Dec 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Benign
-0.020
T
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
D;.
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.80
T;T
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.32
T;T
MetaSVM
Uncertain
0.40
D
MutationAssessor
Benign
1.3
L;L
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.8
D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.017
D;D
Sift4G
Benign
0.11
T;T
Polyphen
0.72
P;D
Vest4
0.45
MVP
0.80
MPC
1.1
ClinPred
0.47
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.76
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374132023; hg19: chr7-128480968; API