chr7-128857174-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001458.5(FLNC):ā€‹c.7618G>Cā€‹(p.Val2540Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 33)
Exomes š‘“: 0.000034 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.01
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]
FLNC-AS1 (HGNC:53474): (FLNC antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.763
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FLNCNM_001458.5 linkuse as main transcriptc.7618G>C p.Val2540Leu missense_variant 46/48 ENST00000325888.13 NP_001449.3
FLNC-AS1NR_149055.1 linkuse as main transcriptn.103-3777C>G intron_variant, non_coding_transcript_variant
FLNCNM_001127487.2 linkuse as main transcriptc.7519G>C p.Val2507Leu missense_variant 45/47 NP_001120959.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkuse as main transcriptc.7618G>C p.Val2540Leu missense_variant 46/481 NM_001458.5 ENSP00000327145 P3Q14315-1
FLNCENST00000346177.6 linkuse as main transcriptc.7519G>C p.Val2507Leu missense_variant 45/471 ENSP00000344002 A1Q14315-2
FLNC-AS1ENST00000469965.1 linkuse as main transcriptn.103-3777C>G intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000322
AC:
8
AN:
248350
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
134868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000714
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461808
Hom.:
0
Cov.:
33
AF XY:
0.0000316
AC XY:
23
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000432
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000849
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000331
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023FLNC: PM2:Supporting, PP3 -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 28, 2022- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 23, 2024The p.V2540L variant (also known as c.7618G>C), located in coding exon 46 of the FLNC gene, results from a G to C substitution at nucleotide position 7618. The valine at codon 2540 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. 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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 17, 2023In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLNC protein function. ClinVar contains an entry for this variant (Variation ID: 539429). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). This variant is present in population databases (rs746349463, gnomAD 0.008%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2540 of the FLNC protein (p.Val2540Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.76
D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Benign
1.9
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-2.4
N;N
REVEL
Pathogenic
0.78
Sift
Benign
0.20
T;T
Sift4G
Benign
0.072
T;T
Polyphen
0.97
D;D
Vest4
0.61
MutPred
0.69
Loss of glycosylation at T2541 (P = 0.1583);.;
MVP
0.82
MPC
1.7
ClinPred
0.50
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.51
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs746349463; hg19: chr7-128497228; API