chr7-128840069-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001458.5(FLNC):​c.1458C>A​(p.Pro486Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,614,004 control chromosomes in the GnomAD database, including 6,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2349 hom., cov: 33)
Exomes 𝑓: 0.038 ( 4338 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.119

Publications

16 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 -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant 7-128840069-C-A is Benign according to our data. Variant chr7-128840069-C-A is described in ClinVar as Benign. ClinVar VariationId is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.119 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.1458C>A p.Pro486Pro synonymous_variant Exon 9 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.1458C>A p.Pro486Pro synonymous_variant Exon 9 of 47 NP_001120959.1 Q14315-2Q59H94

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.1458C>A p.Pro486Pro synonymous_variant Exon 9 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1

Frequencies

GnomAD3 genomes
AF:
0.116
AC:
17700
AN:
152176
Hom.:
2343
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.308
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.0842
Gnomad ASJ
AF:
0.0265
Gnomad EAS
AF:
0.302
Gnomad SAS
AF:
0.0794
Gnomad FIN
AF:
0.0197
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.0175
Gnomad OTH
AF:
0.0985
GnomAD2 exomes
AF:
0.0814
AC:
20301
AN:
249396
AF XY:
0.0733
show subpopulations
Gnomad AFR exome
AF:
0.311
Gnomad AMR exome
AF:
0.127
Gnomad ASJ exome
AF:
0.0253
Gnomad EAS exome
AF:
0.321
Gnomad FIN exome
AF:
0.0257
Gnomad NFE exome
AF:
0.0182
Gnomad OTH exome
AF:
0.0541
GnomAD4 exome
AF:
0.0381
AC:
55618
AN:
1461710
Hom.:
4338
Cov.:
32
AF XY:
0.0378
AC XY:
27485
AN XY:
727168
show subpopulations
African (AFR)
AF:
0.309
AC:
10349
AN:
33480
American (AMR)
AF:
0.123
AC:
5500
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0252
AC:
658
AN:
26136
East Asian (EAS)
AF:
0.280
AC:
11126
AN:
39696
South Asian (SAS)
AF:
0.0701
AC:
6047
AN:
86252
European-Finnish (FIN)
AF:
0.0256
AC:
1362
AN:
53266
Middle Eastern (MID)
AF:
0.0310
AC:
179
AN:
5768
European-Non Finnish (NFE)
AF:
0.0153
AC:
17021
AN:
1111998
Other (OTH)
AF:
0.0559
AC:
3376
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
3066
6131
9197
12262
15328
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
992
1984
2976
3968
4960
<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:
0.116
AC:
17732
AN:
152294
Hom.:
2349
Cov.:
33
AF XY:
0.116
AC XY:
8603
AN XY:
74466
show subpopulations
African (AFR)
AF:
0.308
AC:
12794
AN:
41532
American (AMR)
AF:
0.0839
AC:
1285
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.0265
AC:
92
AN:
3470
East Asian (EAS)
AF:
0.301
AC:
1557
AN:
5174
South Asian (SAS)
AF:
0.0789
AC:
381
AN:
4830
European-Finnish (FIN)
AF:
0.0197
AC:
209
AN:
10628
Middle Eastern (MID)
AF:
0.0272
AC:
8
AN:
294
European-Non Finnish (NFE)
AF:
0.0176
AC:
1194
AN:
68030
Other (OTH)
AF:
0.0993
AC:
210
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
691
1382
2074
2765
3456
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
172
344
516
688
860
<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:
0.0561
Hom.:
990
Bravo
AF:
0.132
Asia WGS
AF:
0.178
AC:
619
AN:
3478
EpiCase
AF:
0.0158
EpiControl
AF:
0.0163

ClinVar

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

Submissions by phenotype

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

- -

Feb 12, 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.Pro486Pro in exon 9 of FLNC: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 28.9% (1144/3952) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2291563). -

Apr 10, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Dec 13, 2017
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Dec 26, 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
-0.35
CADD
Benign
12
DANN
Benign
0.76
PhyloP100
0.12
Mutation Taster
=93/7
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: rs2291563; hg19: chr7-128480123; COSMIC: COSV57953400; COSMIC: COSV57953400; API