dbSNP rs149474376: FLNC:p.Asp187Asp (chr7-128835534-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001458.5(FLNC):c.561C>T(p.Asp187Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,542 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 7 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.83

Publications

0 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=-0.66).

BP6

Variant 7-128835534-C-T is Benign according to our data. Variant chr7-128835534-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.83 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00177 (269/152332) while in subpopulation NFE AF = 0.00278 (189/68030). AF 95% confidence interval is 0.00245. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 269 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.561C>T	p.Asp187Asp	synonymous	Exon 2 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.561C>T	p.Asp187Asp	synonymous	Exon 2 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.561C>T	p.Asp187Asp	synonymous	Exon 2 of 48	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6	TSL:1	c.561C>T	p.Asp187Asp	synonymous	Exon 2 of 47	ENSP00000344002.6	Q14315-2
FLNC	ENST00000950263.1		c.561C>T	p.Asp187Asp	synonymous	Exon 2 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

269

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00233

AC:

576

AN:

246908

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.000697

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00473

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.00249

GnomAD4 exome

AF:

0.00155

AC:

2260

AN:

1461210

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1240

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00335

AC:

289

AN:

86256

European-Finnish (FIN)

AF:

0.00506

AC:

267

AN:

52774

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00140

AC:

1557

AN:

1111990

Other (OTH)

AF:

0.00139

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

133

266

400

533

666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00177

AC:

269

AN:

152332

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41580

American (AMR)

AF:

0.000588

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00278

AC:

189

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00230

Hom.:

Bravo

AF:

0.00116

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 (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

-0.66

CADD

Benign

0.76

(source)

DANN

Benign

0.65

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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