NM_001458.5:c.720T>C

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.720T>C(p.Ile240Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,948 control chromosomes in the GnomAD database, including 10,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1008 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9446 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.68

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: G2P, ClinGen, Ambry Genetics
myofibrillar myopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
myofibrillar myopathy 5
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy 26
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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=-0.78).

BP6

Variant 7-128837418-T-C is Benign according to our data. Variant chr7-128837418-T-C is described in ClinVar as Benign. ClinVar VariationId is 129096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.68 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 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.720T>C	p.Ile240Ile	synonymous	Exon 4 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.720T>C	p.Ile240Ile	synonymous	Exon 4 of 47	NP_001120959.1	Q14315-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.720T>C	p.Ile240Ile	synonymous	Exon 4 of 48	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6	TSL:1	c.720T>C	p.Ile240Ile	synonymous	Exon 4 of 47	ENSP00000344002.6	Q14315-2
FLNC	ENST00000950263.1		c.720T>C	p.Ile240Ile	synonymous	Exon 4 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16947

AN:

152058

Hom.:

1009

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.0625

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.155

Gnomad FIN

AF:

0.0963

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.122

GnomAD2 exomes

AF:

0.105

AC:

26298

AN:

249724

AF XY:

0.108

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.0477

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.0944

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.112

AC:

164189

AN:

1461772

Hom.:

9446

Cov.:

AF XY:

0.113

AC XY:

82425

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.126

AC:

4233

AN:

33468

American (AMR)

AF:

0.0522

AC:

2335

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2817

AN:

26136

East Asian (EAS)

AF:

0.116

AC:

4598

AN:

39700

South Asian (SAS)

AF:

0.142

AC:

12247

AN:

86258

European-Finnish (FIN)

AF:

0.103

AC:

5472

AN:

53382

Middle Eastern (MID)

AF:

0.0869

AC:

501

AN:

5768

European-Non Finnish (NFE)

AF:

0.113

AC:

125125

AN:

1111948

Other (OTH)

AF:

0.114

AC:

6861

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

9675

19350

29026

38701

48376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4594

9188

13782

18376

22970

<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:

0.112

AC:

16972

AN:

152176

Hom.:

1008

Cov.:

AF XY:

0.111

AC XY:

8226

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.125

AC:

5170

AN:

41490

American (AMR)

AF:

0.0623

AC:

954

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

410

AN:

3468

East Asian (EAS)

AF:

0.111

AC:

576

AN:

5170

South Asian (SAS)

AF:

0.154

AC:

744

AN:

4826

European-Finnish (FIN)

AF:

0.0963

AC:

1023

AN:

10620

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7739

AN:

67978

Other (OTH)

AF:

0.124

AC:

263

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

818

1636

2455

3273

4091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.111

Hom.:

1427

Bravo

AF:

0.108

Asia WGS

AF:

0.153

AC:

532

AN:

3478

EpiCase

AF:

0.118

EpiControl

AF:

0.111

ClinVar

ClinVar submissions

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

-0.78

CADD

Benign

0.47

(source)

DANN

Benign

0.60

PhyloP100

-2.7

Mutation Taster

=100/0

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