rs2291562

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.1032C>T(p.Val344Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,613,168 control chromosomes in the GnomAD database, including 7,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2080 hom., cov: 33)

Exomes 𝑓: 0.056 ( 4963 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.12

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=-0.51).

BP6

Variant 7-128838049-C-T is Benign according to our data. Variant chr7-128838049-C-T is described in ClinVar as Benign. ClinVar VariationId is 129078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.12 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 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.1032C>T	p.Val344Val	synonymous	Exon 6 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.1032C>T	p.Val344Val	synonymous	Exon 6 of 47	NP_001120959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.1032C>T	p.Val344Val	synonymous	Exon 6 of 48	ENSP00000327145.8
FLNC	ENST00000346177.6	TSL:1	c.1032C>T	p.Val344Val	synonymous	Exon 6 of 47	ENSP00000344002.6
FLNC	ENST00000950263.1		c.1032C>T	p.Val344Val	synonymous	Exon 6 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18415

AN:

151916

Hom.:

2080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.0939

Gnomad FIN

AF:

0.0209

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0389

Gnomad OTH

AF:

0.0987

GnomAD2 exomes

AF:

0.0957

AC:

23877

AN:

249424

AF XY:

0.0881

show subpopulations

Gnomad AFR exome

AF:

0.285

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.325

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0407

Gnomad OTH exome

AF:

0.0748

GnomAD4 exome

AF:

0.0556

AC:

81243

AN:

1461130

Hom.:

4963

Cov.:

AF XY:

0.0554

AC XY:

40291

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.279

AC:

9338

AN:

33434

American (AMR)

AF:

0.147

AC:

6585

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

475

AN:

26136

East Asian (EAS)

AF:

0.289

AC:

11461

AN:

39692

South Asian (SAS)

AF:

0.0841

AC:

7255

AN:

86238

European-Finnish (FIN)

AF:

0.0276

AC:

1472

AN:

53366

Middle Eastern (MID)

AF:

0.0425

AC:

244

AN:

5738

European-Non Finnish (NFE)

AF:

0.0363

AC:

40361

AN:

1111448

Other (OTH)

AF:

0.0671

AC:

4052

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

4656

9311

13967

18622

23278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1826

3652

5478

7304

9130

<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:

0.121

AC:

18423

AN:

152038

Hom.:

2080

Cov.:

AF XY:

0.120

AC XY:

8949

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.282

AC:

11679

AN:

41418

American (AMR)

AF:

0.102

AC:

1559

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.308

AC:

1589

AN:

5166

South Asian (SAS)

AF:

0.0935

AC:

450

AN:

4814

European-Finnish (FIN)

AF:

0.0209

AC:

222

AN:

10602

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0389

AC:

2645

AN:

67964

Other (OTH)

AF:

0.0981

AC:

207

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

740

1480

2219

2959

3699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.0689

Hom.:

1226

Bravo

AF:

0.137

Asia WGS

AF:

0.179

AC:

619

AN:

3478

EpiCase

AF:

0.0363

EpiControl

AF:

0.0401

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

-0.51

CADD

Benign

1.4

(source)

DANN

Benign

0.74

PhyloP100

-4.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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