rs183104951

Positions:

chr7-128858394-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001458.5(FLNC):c.8049C>T(p.Tyr2683=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,593,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.43

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 7-128858394-C-T is Benign according to our data. Variant chr7-128858394-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 384610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.43 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00163 (247/151852) while in subpopulation AFR AF= 0.00493 (204/41354). AF 95% confidence interval is 0.00438. There are 1 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 247 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FLNC	NM_001458.5 linkuse as main transcript	c.8049C>T	p.Tyr2683=	synonymous_variant	48/48	ENST00000325888.13	NP_001449.3
FLNC-AS1	NR_149055.1 linkuse as main transcript	n.102+4131G>A		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2 linkuse as main transcript	c.7950C>T	p.Tyr2650=	synonymous_variant	47/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.8049C>T	p.Tyr2683=	synonymous_variant	48/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.7950C>T	p.Tyr2650=	synonymous_variant	47/47	1		ENSP00000344002	A1	Q14315-2
FLNC-AS1	ENST00000469965.1 linkuse as main transcript	n.102+4131G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

247

AN:

151734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00495

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000464

AC:

115

AN:

247918

Hom.:

AF XY:

0.000446

AC XY:

AN XY:

134594

show subpopulations

Gnomad AFR exome

AF:

0.00373

Gnomad AMR exome

AF:

0.000554

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000467

AC:

673

AN:

1442022

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

315

AN XY:

718524

show subpopulations

Gnomad4 AFR exome

AF:

0.00437

Gnomad4 AMR exome

AF:

0.000471

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.000410

Gnomad4 OTH exome

AF:

0.000704

GnomAD4 genome

AF:

0.00163

AC:

247

AN:

151852

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

114

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00493

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000837

Hom.:

Bravo

AF:

0.00175

EpiCase

AF:

0.000327

EpiControl

AF:

0.000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2023	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 24, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

FLNC: BP4, BP7 -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.28

DANN

Benign

0.82

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