NM_001458.5:c.1600G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001458.5(FLNC):​c.1600G>A​(p.Glu534Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000841 in 1,614,218 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. E534Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00085 ( 3 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 4.23

Publications

8 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 -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07272342).
BP6
Variant 7-128840598-G-A is Benign according to our data. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631. Variant chr7-128840598-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193631.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000788 (120/152336) while in subpopulation NFE AF = 0.00138 (94/68024). AF 95% confidence interval is 0.00116. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High AC in GnomAd4 at 120 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.1600G>A p.Glu534Lys missense_variant Exon 10 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.1600G>A p.Glu534Lys missense_variant Exon 10 of 47 NP_001120959.1 Q14315-2Q59H94

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.1600G>A p.Glu534Lys missense_variant Exon 10 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1

Frequencies

GnomAD3 genomes
AF:
0.000788
AC:
120
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00122
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00138
Gnomad OTH
AF:
0.000955
GnomAD2 exomes
AF:
0.000785
AC:
196
AN:
249574
AF XY:
0.000783
show subpopulations
Gnomad AFR exome
AF:
0.000323
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.000993
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00158
Gnomad NFE exome
AF:
0.00126
Gnomad OTH exome
AF:
0.000495
GnomAD4 exome
AF:
0.000847
AC:
1238
AN:
1461882
Hom.:
3
Cov.:
33
AF XY:
0.000850
AC XY:
618
AN XY:
727240
show subpopulations
African (AFR)
AF:
0.000269
AC:
9
AN:
33480
American (AMR)
AF:
0.0000447
AC:
2
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.000880
AC:
23
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00169
AC:
90
AN:
53410
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5768
European-Non Finnish (NFE)
AF:
0.000965
AC:
1073
AN:
1112010
Other (OTH)
AF:
0.000646
AC:
39
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
93
186
279
372
465
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
24
48
72
96
120
<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:
0.000788
AC:
120
AN:
152336
Hom.:
0
Cov.:
33
AF XY:
0.000792
AC XY:
59
AN XY:
74488
show subpopulations
African (AFR)
AF:
0.000120
AC:
5
AN:
41570
American (AMR)
AF:
0.00
AC:
0
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00173
AC:
6
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00122
AC:
13
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00138
AC:
94
AN:
68024
Other (OTH)
AF:
0.000945
AC:
2
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
7
14
22
29
36
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:
0.00130
Hom.:
1
Bravo
AF:
0.000589
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000463
AC:
2
ESP6500EA
AF:
0.00106
AC:
9
ExAC
AF:
0.000808
AC:
98

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
Mar 07, 2017
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 16, 2019
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27296017, 28008999) -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

FLNC: BS1 -

not specified Benign:3
Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 03, 2017
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 19, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
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 Benign:1
Jul 30, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Cardiomyopathy Benign:1
May 16, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

FLNC-related disorder Benign:1
Feb 11, 2021
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1
Jan 25, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
Feb 02, 2025
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
0.26
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.073
T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.1
L;L
PhyloP100
4.2
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.19
Sift
Benign
0.70
T;T
Sift4G
Benign
0.73
T;T
Polyphen
0.028
B;B
Vest4
0.77
MVP
0.55
MPC
0.33
ClinPred
0.032
T
GERP RS
3.4
Varity_R
0.10
gMVP
0.68
Mutation Taster
=81/19
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: rs201905890; hg19: chr7-128480652; COSMIC: COSV99064146; COSMIC: COSV99064146; API