7-128842781-C-T

Position:

chr7-128842781-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001458.5(FLNC):c.2390-13C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,612,930 control chromosomes in the GnomAD database, including 1,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 93 hom., cov: 33)

Exomes 𝑓: 0.034 ( 1061 hom. )

Consequence

FLNC
NM_001458.5 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.114

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 7-128842781-C-T is Benign according to our data. Variant chr7-128842781-C-T is described in ClinVar as [Benign]. Clinvar id is 258136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842781-C-T is described in Lovd as [Benign]. Variant chr7-128842781-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0277 (4212/152320) while in subpopulation NFE AF= 0.0379 (2579/68018). AF 95% confidence interval is 0.0367. There are 93 homozygotes in gnomad4. There are 2182 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4212 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.2390-13C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000325888.13
FLNC	NM_001127487.2 linkuse as main transcript	c.2390-13C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.2390-13C>T	splice_polypyrimidine_tract_variant, intron_variant	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.2390-13C>T	splice_polypyrimidine_tract_variant, intron_variant	1		A1	Q14315-2
FLNC	ENST00000388853.3 linkuse as main transcript	n.506-13C>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0277

AC:

4213

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00659

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0312

Gnomad FIN

AF:

0.0811

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0379

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0313

AC:

7716

AN:

246340

Hom.:

195

AF XY:

0.0319

AC XY:

4286

AN XY:

134202

show subpopulations

Gnomad AFR exome

AF:

0.00607

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0204

Gnomad EAS exome

AF:

0.000727

Gnomad SAS exome

AF:

0.0304

Gnomad FIN exome

AF:

0.0765

Gnomad NFE exome

AF:

0.0389

Gnomad OTH exome

AF:

0.0279

GnomAD4 exome

AF:

0.0345

AC:

50322

AN:

1460610

Hom.:

1061

Cov.:

AF XY:

0.0348

AC XY:

25250

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00487

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.0311

Gnomad4 FIN exome

AF:

0.0710

Gnomad4 NFE exome

AF:

0.0369

Gnomad4 OTH exome

AF:

0.0271

GnomAD4 genome

AF:

0.0277

AC:

4212

AN:

152320

Hom.:

Cov.:

AF XY:

0.0293

AC XY:

2182

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00657

Gnomad4 AMR

AF:

0.0146

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0313

Gnomad4 FIN

AF:

0.0811

Gnomad4 NFE

AF:

0.0379

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0306

Hom.:

Bravo

AF:

0.0211

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	2390-13C>T in intron 15 of FLNC: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (296/8414) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs78086167). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.2

DANN

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over