7-128841142-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001458.5(FLNC):c.1814-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0776 in 1,609,970 control chromosomes in the GnomAD database, including 12,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 4046 hom., cov: 32)

Exomes 𝑓: 0.069 ( 8311 hom. )

Consequence

FLNC
NM_001458.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.251

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 7-128841142-T-C is Benign according to our data. Variant chr7-128841142-T-C is described in ClinVar as [Benign]. Clinvar id is 258128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.1814-28T>C		intron_variant	Intron 11 of 47	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.1814-28T>C		intron_variant	Intron 11 of 46		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.1814-28T>C		intron_variant	Intron 11 of 47	1	NM_001458.5	ENSP00000327145.8		Q14315-1

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24719

AN:

151794

Hom.:

4033

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.353

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.0215

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0425

Gnomad OTH

AF:

0.127

GnomAD2 exomes

AF:

0.120

AC:

29515

AN:

246554

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.405

Gnomad AMR exome

AF:

0.159

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.362

Gnomad FIN exome

AF:

0.0267

Gnomad NFE exome

AF:

0.0437

Gnomad OTH exome

AF:

0.0885

GnomAD4 exome

AF:

0.0687

AC:

100217

AN:

1458058

Hom.:

8311

Cov.:

AF XY:

0.0701

AC XY:

50817

AN XY:

725196

show subpopulations

African (AFR)

AF:

0.407

AC:

13619

AN:

33428

American (AMR)

AF:

0.155

AC:

6934

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.0186

AC:

483

AN:

25942

East Asian (EAS)

AF:

0.334

AC:

13258

AN:

39682

South Asian (SAS)

AF:

0.167

AC:

14367

AN:

85904

European-Finnish (FIN)

AF:

0.0276

AC:

1451

AN:

52510

Middle Eastern (MID)

AF:

0.0508

AC:

275

AN:

5410

European-Non Finnish (NFE)

AF:

0.0401

AC:

44531

AN:

1110362

Other (OTH)

AF:

0.0880

AC:

5299

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

5149

10298

15448

20597

25746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.163

AC:

24758

AN:

151912

Hom.:

4046

Cov.:

AF XY:

0.162

AC XY:

12048

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.405

AC:

16768

AN:

41386

American (AMR)

AF:

0.121

AC:

1843

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3466

East Asian (EAS)

AF:

0.352

AC:

1808

AN:

5130

South Asian (SAS)

AF:

0.183

AC:

880

AN:

4810

European-Finnish (FIN)

AF:

0.0215

AC:

228

AN:

10598

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0425

AC:

2888

AN:

67930

Other (OTH)

AF:

0.126

AC:

267

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

856

1713

2569

3426

4282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0995

Hom.:

385

Bravo

AF:

0.180

Asia WGS

AF:

0.267

AC:

925

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.9

(source)

DANN

Benign

0.39

PhyloP100

0.25

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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7-128841142-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over