rs28379666

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001458.5(FLNC):c.8118C>T(p.Leu2706=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,608,226 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. LI2706LI) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 46 hom., cov: 31)

Exomes 𝑓: 0.0040 ( 113 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0650

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 7-128858463-C-T is Benign according to our data. Variant chr7-128858463-C-T is described in ClinVar as [Benign]. Clinvar id is 129100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128858463-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.065 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0153 (2330/152008) while in subpopulation AFR AF= 0.044 (1820/41364). AF 95% confidence interval is 0.0423. There are 46 homozygotes in gnomad4. There are 1090 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd at 2326 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FLNC	NM_001458.5 linkuse as main transcript	c.8118C>T	p.Leu2706=	synonymous_variant	48/48	ENST00000325888.13
FLNC-AS1	NR_149055.1 linkuse as main transcript	n.102+4062G>A		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2 linkuse as main transcript	c.8019C>T	p.Leu2673=	synonymous_variant	47/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.8118C>T	p.Leu2706=	synonymous_variant	48/48	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.8019C>T	p.Leu2673=	synonymous_variant	47/47	1		A1	Q14315-2
FLNC-AS1	ENST00000469965.1 linkuse as main transcript	n.102+4062G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2326

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0440

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0153

Gnomad SAS

AF:

0.0279

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00949

AC:

2368

AN:

249484

Hom.:

AF XY:

0.00996

AC XY:

1348

AN XY:

135354

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0121

Gnomad SAS exome

AF:

0.0343

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00230

Gnomad OTH exome

AF:

0.00644

GnomAD4 exome

AF:

0.00403

AC:

5863

AN:

1456218

Hom.:

113

Cov.:

AF XY:

0.00460

AC XY:

3331

AN XY:

724280

show subpopulations

Gnomad4 AFR exome

AF:

0.0261

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0166

Gnomad4 SAS exome

AF:

0.0217

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00188

Gnomad4 OTH exome

AF:

0.00523

GnomAD4 genome

AF:

0.0153

AC:

2330

AN:

152008

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1090

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0440

Gnomad4 AMR

AF:

0.00497

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0153

Gnomad4 SAS

AF:

0.0279

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00837

Hom.:

Bravo

AF:

0.0166

EpiCase

AF:

0.00267

EpiControl

AF:

0.00284

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

-0.43

Cadd

Benign

7.7

Dann

Benign

0.80

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