7-128851443-C-T

Position:

chr7-128851443-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.5669-12C>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 0.0336 in 1,613,920 control chromosomes in the GnomAD database, including 1,150 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 ( 1057 hom. )

Consequence

FLNC
NM_001458.5 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003501

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0410

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 7-128851443-C-T is Benign according to our data. Variant chr7-128851443-C-T is described in ClinVar as [Benign]. Clinvar id is 258149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128851443-C-T is described in Lovd as [Benign]. Variant chr7-128851443-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0275 (4189/152324) while in subpopulation NFE AF= 0.0377 (2567/68028). AF 95% confidence interval is 0.0365. There are 93 homozygotes in gnomad4. There are 2170 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
FLNC	NM_001458.5 linkuse as main transcript	c.5669-12C>T	splice_polypyrimidine_tract_variant, intron_variant		ENST00000325888.13
FLNC-AS1	NR_149055.1 linkuse as main transcript	n.273G>A	non_coding_transcript_exon_variant	3/4
FLNC	NM_001127487.2 linkuse as main transcript	c.5570-12C>T	splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.5669-12C>T	splice_polypyrimidine_tract_variant, intron_variant		1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.5570-12C>T	splice_polypyrimidine_tract_variant, intron_variant		1		A1	Q14315-2
FLNC-AS1	ENST00000469965.1 linkuse as main transcript	n.273G>A	non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes

AF:

0.0275

AC:

4190

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00644

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.0811

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0377

Gnomad OTH

AF:

0.0181

GnomAD3 exomes

AF:

0.0312

AC:

7794

AN:

249420

Hom.:

208

AF XY:

0.0318

AC XY:

4309

AN XY:

135356

show subpopulations

Gnomad AFR exome

AF:

0.00594

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0204

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.0765

Gnomad NFE exome

AF:

0.0388

Gnomad OTH exome

AF:

0.0278

GnomAD4 exome

AF:

0.0343

AC:

50078

AN:

1461596

Hom.:

1057

Cov.:

AF XY:

0.0346

AC XY:

25148

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00469

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0192

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0311

Gnomad4 FIN exome

AF:

0.0710

Gnomad4 NFE exome

AF:

0.0367

Gnomad4 OTH exome

AF:

0.0269

GnomAD4 genome

AF:

0.0275

AC:

4189

AN:

152324

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

2170

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00642

Gnomad4 AMR

AF:

0.0146

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0309

Gnomad4 FIN

AF:

0.0811

Gnomad4 NFE

AF:

0.0377

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0318

Hom.:

Bravo

AF:

0.0210

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	5669-12C>T in intron 34 of FLNC: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (300/8532) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs79790270). -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

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

-0.71

CADD

Benign

6.4

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00035

dbscSNV1_RF

Benign

0.030

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