chr7-128846392-C-T

Variant names:

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.4056C>T(p.Arg1352Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,611,006 control chromosomes in the GnomAD database, including 5,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.090 ( 1043 hom., cov: 33)

Exomes 𝑓: 0.053 ( 4134 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -8.61

Publications

12 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 7-128846392-C-T is Benign according to our data. Variant chr7-128846392-C-T is described in ClinVar as Benign. ClinVar VariationId is 129089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.4056C>T	p.Arg1352Arg	synonymous	Exon 23 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.4056C>T	p.Arg1352Arg	synonymous	Exon 23 of 47	NP_001120959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.4056C>T	p.Arg1352Arg	synonymous	Exon 23 of 48	ENSP00000327145.8
FLNC	ENST00000346177.6	TSL:1	c.4056C>T	p.Arg1352Arg	synonymous	Exon 23 of 47	ENSP00000344002.6
FLNC	ENST00000950263.1		c.4053C>T	p.Arg1351Arg	synonymous	Exon 23 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.0895

AC:

13616

AN:

152072

Hom.:

1038

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0897

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.312

Gnomad SAS

AF:

0.0939

Gnomad FIN

AF:

0.0209

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0385

Gnomad OTH

AF:

0.0766

GnomAD2 exomes

AF:

0.0888

AC:

21928

AN:

247042

AF XY:

0.0827

show subpopulations

Gnomad AFR exome

AF:

0.173

Gnomad AMR exome

AF:

0.147

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.0264

Gnomad NFE exome

AF:

0.0406

Gnomad OTH exome

AF:

0.0707

GnomAD4 exome

AF:

0.0531

AC:

77424

AN:

1458816

Hom.:

4134

Cov.:

AF XY:

0.0532

AC XY:

38649

AN XY:

725858

show subpopulations

African (AFR)

AF:

0.177

AC:

5936

AN:

33470

American (AMR)

AF:

0.142

AC:

6369

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

474

AN:

26134

East Asian (EAS)

AF:

0.293

AC:

11643

AN:

39698

South Asian (SAS)

AF:

0.0844

AC:

7283

AN:

86258

European-Finnish (FIN)

AF:

0.0273

AC:

1377

AN:

50482

Middle Eastern (MID)

AF:

0.0413

AC:

238

AN:

5768

European-Non Finnish (NFE)

AF:

0.0364

AC:

40432

AN:

1111910

Other (OTH)

AF:

0.0608

AC:

3672

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4524

9048

13572

18096

22620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1796

3592

5388

7184

8980

<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:

0.0896

AC:

13632

AN:

152190

Hom.:

1043

Cov.:

AF XY:

0.0901

AC XY:

6708

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.172

AC:

7131

AN:

41498

American (AMR)

AF:

0.0894

AC:

1368

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3468

East Asian (EAS)

AF:

0.311

AC:

1608

AN:

5166

South Asian (SAS)

AF:

0.0936

AC:

451

AN:

4818

European-Finnish (FIN)

AF:

0.0209

AC:

222

AN:

10622

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0385

AC:

2620

AN:

67994

Other (OTH)

AF:

0.0762

AC:

161

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

597

1194

1791

2388

2985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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:

0.0571

Hom.:

222

Bravo

AF:

0.102

Asia WGS

AF:

0.173

AC:

601

AN:

3478

EpiCase

AF:

0.0359

EpiControl

AF:

0.0395

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (2)

Cardiovascular phenotype (1)

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.032

(source)

DANN

Benign

0.83

PhyloP100

-8.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=84/16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over