NM_001458.5:c.3973C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001458.5(FLNC):​c.3973C>T​(p.Leu1325Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,613,268 control chromosomes in the GnomAD database, including 36,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 8234 hom., cov: 33)
Exomes 𝑓: 0.18 ( 28004 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.393

Publications

20 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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 7-128846309-C-T is Benign according to our data. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in CliVar as Benign. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.393 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.3973C>T p.Leu1325Leu synonymous_variant Exon 23 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.3973C>T p.Leu1325Leu synonymous_variant Exon 23 of 47 NP_001120959.1 Q14315-2Q59H94

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.3973C>T p.Leu1325Leu synonymous_variant Exon 23 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1

Frequencies

GnomAD3 genomes
AF:
0.281
AC:
42645
AN:
151926
Hom.:
8201
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.543
Gnomad AMI
AF:
0.0868
Gnomad AMR
AF:
0.191
Gnomad ASJ
AF:
0.151
Gnomad EAS
AF:
0.426
Gnomad SAS
AF:
0.217
Gnomad FIN
AF:
0.165
Gnomad MID
AF:
0.136
Gnomad NFE
AF:
0.164
Gnomad OTH
AF:
0.249
GnomAD2 exomes
AF:
0.219
AC:
54420
AN:
248170
AF XY:
0.211
show subpopulations
Gnomad AFR exome
AF:
0.551
Gnomad AMR exome
AF:
0.209
Gnomad ASJ exome
AF:
0.147
Gnomad EAS exome
AF:
0.423
Gnomad FIN exome
AF:
0.170
Gnomad NFE exome
AF:
0.167
Gnomad OTH exome
AF:
0.199
GnomAD4 exome
AF:
0.181
AC:
264678
AN:
1461224
Hom.:
28004
Cov.:
35
AF XY:
0.181
AC XY:
131491
AN XY:
726904
show subpopulations
African (AFR)
AF:
0.553
AC:
18514
AN:
33478
American (AMR)
AF:
0.210
AC:
9390
AN:
44640
Ashkenazi Jewish (ASJ)
AF:
0.142
AC:
3713
AN:
26126
East Asian (EAS)
AF:
0.420
AC:
16667
AN:
39676
South Asian (SAS)
AF:
0.201
AC:
17339
AN:
86234
European-Finnish (FIN)
AF:
0.169
AC:
8969
AN:
53172
Middle Eastern (MID)
AF:
0.146
AC:
844
AN:
5766
European-Non Finnish (NFE)
AF:
0.160
AC:
177489
AN:
1111762
Other (OTH)
AF:
0.195
AC:
11753
AN:
60370
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
13720
27440
41160
54880
68600
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
6584
13168
19752
26336
32920
<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:
0.281
AC:
42729
AN:
152044
Hom.:
8234
Cov.:
33
AF XY:
0.279
AC XY:
20722
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.544
AC:
22523
AN:
41434
American (AMR)
AF:
0.191
AC:
2919
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.151
AC:
526
AN:
3472
East Asian (EAS)
AF:
0.425
AC:
2189
AN:
5150
South Asian (SAS)
AF:
0.217
AC:
1047
AN:
4820
European-Finnish (FIN)
AF:
0.165
AC:
1753
AN:
10612
Middle Eastern (MID)
AF:
0.126
AC:
37
AN:
294
European-Non Finnish (NFE)
AF:
0.164
AC:
11127
AN:
67948
Other (OTH)
AF:
0.251
AC:
529
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1346
2692
4039
5385
6731
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
402
804
1206
1608
2010
<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:
0.221
Hom.:
10388
Bravo
AF:
0.298
Asia WGS
AF:
0.315
AC:
1094
AN:
3478
EpiCase
AF:
0.163
EpiControl
AF:
0.163

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:9
Dec 30, 2015
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 04, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 08, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Aug 15, 2013
Genetic Services Laboratory, University of Chicago
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 13, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Leu1325Leu in exon 23 of FLNC: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 47.5% (2011/4238) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34373805). -

Jul 08, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
Sep 12, 2017
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Cardiovascular phenotype Benign:1
Dec 24, 2018
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as 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 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
2.5
DANN
Benign
0.84
PhyloP100
-0.39
Mutation Taster
=100/0
polymorphism (auto)

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: rs34373805; hg19: chr7-128486363; COSMIC: COSV57955951; COSMIC: COSV57955951; API