7-128858227-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001458.5(FLNC):c.7990+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 1,401,816 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

FLNC
NM_001458.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0330

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 links:

FLNC-AS1 (HGNC:53474): (FLNC antisense RNA 1)

FLNC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 7-128858227-G-A is Benign according to our data. Variant chr7-128858227-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 539492.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FLNC	NM_001458.5	MANE Select	c.7990+10G>A	intron	N/A	NP_001449.3
FLNC	NM_001127487.2		c.7891+10G>A	intron	N/A	NP_001120959.1
FLNC-AS1	NR_149055.1		n.102+4298C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7990+10G>A	intron	N/A	ENSP00000327145.8
FLNC	ENST00000346177.6	TSL:1	c.7891+10G>A	intron	N/A	ENSP00000344002.6
FLNC	ENST00000714183.1		c.7852+10G>A	intron	N/A	ENSP00000519472.1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000445

AC:

AN:

202442

AF XY:

0.0000181

show subpopulations

Gnomad AFR exome

AF:

0.000166

Gnomad AMR exome

AF:

0.000105

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000457

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000368

AC:

AN:

1249978

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

631428

show subpopulations

African (AFR)

AF:

0.000465

AC:

AN:

30120

American (AMR)

AF:

0.0000690

AC:

AN:

43466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24622

East Asian (EAS)

AF:

0.00

AC:

AN:

38520

South Asian (SAS)

AF:

0.0000245

AC:

AN:

81614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4530

European-Non Finnish (NFE)

AF:

0.0000260

AC:

AN:

921694

Other (OTH)

AF:

0.0000564

AC:

AN:

53168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000145

AC:

AN:

151838

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74154

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000339

AC:

AN:

41280

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000209

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67938

Other (OTH)

AF:

0.000478

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000278793), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.386

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:

0.0000480

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:1

Feb 13, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant

Benign:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.0

(source)

DANN

Benign

0.74

PhyloP100

-0.033

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over