rs2291568

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.4431G>A(p.Leu1477Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.076 in 1,613,544 control chromosomes in the GnomAD database, including 11,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 3591 hom., cov: 34)

Exomes 𝑓: 0.068 ( 7902 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.313

Publications

14 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=-0.49).

BP6

Variant 7-128847839-G-A is Benign according to our data. Variant chr7-128847839-G-A is described in ClinVar as Benign. ClinVar VariationId is 129090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.313 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 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.4431G>A	p.Leu1477Leu	synonymous	Exon 25 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.4431G>A	p.Leu1477Leu	synonymous	Exon 25 of 47	NP_001120959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.4431G>A	p.Leu1477Leu	synonymous	Exon 25 of 48	ENSP00000327145.8
FLNC	ENST00000346177.6	TSL:1	c.4431G>A	p.Leu1477Leu	synonymous	Exon 25 of 47	ENSP00000344002.6
FLNC	ENST00000950263.1		c.4428G>A	p.Leu1476Leu	synonymous	Exon 25 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23559

AN:

152138

Hom.:

3584

Cov.:

show subpopulations

Gnomad AFR

AF:

0.378

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0423

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.117

AC:

29165

AN:

248632

AF XY:

0.111

show subpopulations

Gnomad AFR exome

AF:

0.381

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.362

Gnomad FIN exome

AF:

0.0267

Gnomad NFE exome

AF:

0.0436

Gnomad OTH exome

AF:

0.0874

GnomAD4 exome

AF:

0.0678

AC:

99122

AN:

1461290

Hom.:

7902

Cov.:

AF XY:

0.0693

AC XY:

50397

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.381

AC:

12749

AN:

33478

American (AMR)

AF:

0.154

AC:

6884

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

474

AN:

26108

East Asian (EAS)

AF:

0.334

AC:

13244

AN:

39696

South Asian (SAS)

AF:

0.167

AC:

14419

AN:

86236

European-Finnish (FIN)

AF:

0.0277

AC:

1474

AN:

53174

Middle Eastern (MID)

AF:

0.0493

AC:

283

AN:

5736

European-Non Finnish (NFE)

AF:

0.0400

AC:

44454

AN:

1111780

Other (OTH)

AF:

0.0852

AC:

5141

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

5517

11034

16550

22067

27584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2098

4196

6294

8392

10490

<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:

0.155

AC:

23583

AN:

152254

Hom.:

3591

Cov.:

AF XY:

0.154

AC XY:

11477

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.378

AC:

15681

AN:

41508

American (AMR)

AF:

0.116

AC:

1769

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.352

AC:

1821

AN:

5180

South Asian (SAS)

AF:

0.182

AC:

881

AN:

4828

European-Finnish (FIN)

AF:

0.0214

AC:

227

AN:

10628

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0423

AC:

2876

AN:

68008

Other (OTH)

AF:

0.120

AC:

254

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

858

1717

2575

3434

4292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.0741

Hom.:

1357

Bravo

AF:

0.172

Asia WGS

AF:

0.265

AC:

920

AN:

3478

EpiCase

AF:

0.0397

EpiControl

AF:

0.0434

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

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

-0.49

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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