chr7-128838651-G-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001458.5(FLNC):​c.1259G>A​(p.Arg420Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,612,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. R420W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.07

Publications

3 publications found
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 Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
  • myofibrillar myopathy 5
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
  • hypertrophic cardiomyopathy 26
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
  • distal myopathy with posterior leg and anterior hand involvement
    Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
  • familial isolated restrictive cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • heart conduction disease
    Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16178036).
BP6
Variant 7-128838651-G-A is Benign according to our data. Variant chr7-128838651-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 539342.
BS2
High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.1259G>A p.Arg420Gln missense_variant Exon 8 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.1259G>A p.Arg420Gln missense_variant Exon 8 of 47 NP_001120959.1 Q14315-2Q59H94

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.1259G>A p.Arg420Gln missense_variant Exon 8 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152224
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000605
AC:
15
AN:
247772
AF XY:
0.0000444
show subpopulations
Gnomad AFR exome
AF:
0.000131
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.000332
GnomAD4 exome
AF:
0.0000397
AC:
58
AN:
1460754
Hom.:
0
Cov.:
33
AF XY:
0.0000317
AC XY:
23
AN XY:
726690
show subpopulations
African (AFR)
AF:
0.000119
AC:
4
AN:
33480
American (AMR)
AF:
0.000179
AC:
8
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.000252
AC:
10
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52310
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000279
AC:
31
AN:
1112000
Other (OTH)
AF:
0.0000828
AC:
5
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152224
Hom.:
1
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74356
show subpopulations
African (AFR)
AF:
0.000482
AC:
20
AN:
41452
American (AMR)
AF:
0.0000654
AC:
1
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.000117
ESP6500AA
AF:
0.000466
AC:
2
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.0000578
AC:
7

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:2
Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 23, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R420Q variant (also known as c.1259G>A), located in coding exon 8 of the FLNC gene, results from a G to A substitution at nucleotide position 1259. The arginine at codon 420 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Uncertain:1
Jul 28, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
Dec 31, 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
Benign
0.085
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.29
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T;.
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.6
L;L
PhyloP100
3.1
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.22
Sift
Benign
0.64
T;T
Sift4G
Benign
0.29
T;T
Polyphen
0.65
P;P
Vest4
0.43
MVP
0.52
MPC
0.56
ClinPred
0.040
T
GERP RS
5.4
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
3.5
Varity_R
0.054
gMVP
0.33
Mutation Taster
=90/10
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs371410741; hg19: chr7-128478705; COSMIC: COSV57962167; COSMIC: COSV57962167; API