rs149641783

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001458.5(FLNC):c.4022G>A(p.Arg1341Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000827 in 1,613,308 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1341R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 3 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 8.13

Publications

10 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016079754).

BP6

Variant 7-128846358-G-A is Benign according to our data. Variant chr7-128846358-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195741.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000749 (114/152288) while in subpopulation NFE AF = 0.000912 (62/68008). AF 95% confidence interval is 0.000729. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 114 AD gene.

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.4022G>A	p.Arg1341Gln	missense	Exon 23 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.4022G>A	p.Arg1341Gln	missense	Exon 23 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.4022G>A	p.Arg1341Gln	missense	Exon 23 of 48	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6	TSL:1	c.4022G>A	p.Arg1341Gln	missense	Exon 23 of 47	ENSP00000344002.6	Q14315-2
FLNC	ENST00000950263.1		c.4019G>A	p.Arg1340Gln	missense	Exon 23 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000912

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00105

AC:

260

AN:

248756

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00755

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000946

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.000836

AC:

1221

AN:

1461020

Hom.:

Cov.:

AF XY:

0.000923

AC XY:

671

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33480

American (AMR)

AF:

0.00105

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00777

AC:

203

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52576

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000639

AC:

711

AN:

1111994

Other (OTH)

AF:

0.00202

AC:

122

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000749

AC:

114

AN:

152288

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41550

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000912

AC:

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00107

Hom.:

Bravo

AF:

0.000842

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.000933

AC:

113

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

FLNC-related disorder (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

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.016

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.8

PhyloP100

8.1

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.49

Sift

Benign

0.57

Sift4G

Benign

0.55

Polyphen

0.17

Vest4

0.73

MVP

0.71

MPC

0.96

ClinPred

0.052

GERP RS

5.1

Varity_R

0.19

gMVP

0.50

Mutation Taster

=61/39

polymorphism

(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