rs3734972

Variant names:

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.147C>T(p.His49His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,612,946 control chromosomes in the GnomAD database, including 6,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 714 hom., cov: 33)

Exomes 𝑓: 0.088 ( 5983 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.787

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

FLNC links:

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=-0.39).

BP6

Variant 7-128830784-C-T is Benign according to our data. Variant chr7-128830784-C-T is described in ClinVar as Benign. ClinVar VariationId is 129081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.787 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.147C>T	p.His49His	synonymous_variant	Exon 1 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.147C>T	p.His49His	synonymous_variant	Exon 1 of 47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.147C>T	p.His49His	synonymous_variant	Exon 1 of 48	1	NM_001458.5	ENSP00000327145.8		Q14315-1

Frequencies

GnomAD3 genomes

AF:

0.0939

AC:

14287

AN:

152184

Hom.:

712

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0975

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0881

Gnomad ASJ

AF:

0.0985

Gnomad EAS

AF:

0.191

Gnomad SAS

AF:

0.0982

Gnomad FIN

AF:

0.0844

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0865

Gnomad OTH

AF:

0.107

GnomAD2 exomes

AF:

0.0940

AC:

23381

AN:

248698

AF XY:

0.0929

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0866

Gnomad ASJ exome

AF:

0.0908

Gnomad EAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.0835

Gnomad NFE exome

AF:

0.0861

Gnomad OTH exome

AF:

0.0943

GnomAD4 exome

AF:

0.0884

AC:

129166

AN:

1460644

Hom.:

5983

Cov.:

AF XY:

0.0887

AC XY:

64470

AN XY:

726626

show subpopulations

African (AFR)

AF:

0.102

AC:

3406

AN:

33476

American (AMR)

AF:

0.0898

AC:

4011

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0908

AC:

2373

AN:

26124

East Asian (EAS)

AF:

0.183

AC:

7276

AN:

39684

South Asian (SAS)

AF:

0.0876

AC:

7554

AN:

86242

European-Finnish (FIN)

AF:

0.0829

AC:

4349

AN:

52486

Middle Eastern (MID)

AF:

0.0846

AC:

488

AN:

5768

European-Non Finnish (NFE)

AF:

0.0848

AC:

94262

AN:

1111824

Other (OTH)

AF:

0.0902

AC:

5447

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

8310

16620

24931

33241

41551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3540

7080

10620

14160

17700

<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:

0.0939

AC:

14307

AN:

152302

Hom.:

714

Cov.:

AF XY:

0.0939

AC XY:

6995

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0976

AC:

4057

AN:

41552

American (AMR)

AF:

0.0881

AC:

1348

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0985

AC:

342

AN:

3472

East Asian (EAS)

AF:

0.191

AC:

989

AN:

5172

South Asian (SAS)

AF:

0.0979

AC:

473

AN:

4832

European-Finnish (FIN)

AF:

0.0844

AC:

897

AN:

10626

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0865

AC:

5887

AN:

68026

Other (OTH)

AF:

0.108

AC:

229

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

686

1371

2057

2742

3428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0898

Hom.:

1099

Bravo

AF:

0.0949

Asia WGS

AF:

0.145

AC:

506

AN:

3478

EpiCase

AF:

0.0921

EpiControl

AF:

0.0885

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Jan 08, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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.His49His in exon 1 of FLNC: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 11.1% (487/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs3734972). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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 27, 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

-0.39

CADD

Benign

7.7

(source)

DANN

Benign

0.97

PhyloP100

0.79

PromoterAI

-0.085

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over