7-128842700-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001458.5(FLNC):c.2389+2T>G variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000091 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FLNC
NM_001458.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.99

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: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 19, new splice context is: gggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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.2389+2T>G		splice_donor intron	N/A	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.2389+2T>G		splice_donor intron	N/A	NP_001120959.1	Q14315-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLNC	ENST00000325888.13	TSL:1 MANE Select	c.2389+2T>G	splice_donor intron	N/A	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6	TSL:1	c.2389+2T>G	splice_donor intron	N/A	ENSP00000344002.6	Q14315-2
FLNC	ENST00000950263.1		c.2389+2T>G	splice_donor intron	N/A	ENSP00000620322.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

142520

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000653

AC:

AN:

153240

AF XY:

0.0000733

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000178

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000138

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000906

AC:

AN:

1213750

Hom.:

Cov.:

AF XY:

0.0000150

AC XY:

AN XY:

600906

show subpopulations

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

African (AFR)

AF:

0.0000369

AC:

AN:

27108

American (AMR)

AF:

0.00

AC:

AN:

32322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20544

East Asian (EAS)

AF:

0.0000403

AC:

AN:

24816

South Asian (SAS)

AF:

0.0000130

AC:

AN:

77058

European-Finnish (FIN)

AF:

0.0000290

AC:

AN:

34462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4430

European-Non Finnish (NFE)

AF:

0.00000529

AC:

AN:

945190

Other (OTH)

AF:

0.0000418

AC:

AN:

47820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000000188738), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

142520

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69238

African (AFR)

AF:

0.00

AC:

AN:

38726

American (AMR)

AF:

0.00

AC:

AN:

14514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3354

East Asian (EAS)

AF:

0.00

AC:

AN:

4282

South Asian (SAS)

AF:

0.00

AC:

AN:

4030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65398

Other (OTH)

AF:

0.00

AC:

AN:

2006

ExAC

AF:

0.000196

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.97

PhyloP100

8.0

GERP RS

5.5

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: 17

DS_DL_spliceai

1.0

Position offset: -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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over