rs751650734

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001458.5(FLNC):c.5296T>C(p.Trp1766Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000254 in 1,537,034 control chromosomes in the GnomAD database, including 1 homozygotes. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

FLNC
NM_001458.5 missense, splice_region

Scores

Splicing: ADA: 0.1078

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O:1

Conservation

PhyloP100: 5.32

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 Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNC

BS2

High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.5296T>C	p.Trp1766Arg	missense_variant, splice_region_variant	31/48	ENST00000325888.13
FLNC	NM_001127487.2 linkuse as main transcript	c.5200-312T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.5296T>C	p.Trp1766Arg	missense_variant, splice_region_variant	31/48	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.5200-312T>C		intron_variant		1		A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000561

AC:

AN:

142704

Hom.:

AF XY:

0.0000647

AC XY:

AN XY:

77252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

370

AN:

1384772

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

170

AN XY:

684046

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000332

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.000138

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0000268

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2021	At the protein level, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; At the mRNA level, in-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 472101; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31513939) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 20, 2022	- -

Hypertrophic cardiomyopathy 26

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Null variants are enriched in dilated cardiomyopathy and distal myopathy cohorts (MIM#614065), while missense variants mainly in the ROD2 domain, are enriched in hypertrophic cardiomyopathy, familial (HCM) (MIM#617047), restrictive cardiomyopathy, familial (MIM#617047) and myofibrillar myopathy (MIM#609524) (PMID: 32112656) cohorts. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to arginine. However, this variant is close to the intron-exon junction and may have an effect on splicing. (I) 0219 - This variant is non-coding in an alternative transcript. This variant is coding in the ClinVar predominant transcript (NM_001458), but is deep intronic within another transcript (NM_001127487) which is highly expressed in cardiac tissue (GTex). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (21 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. This nucleotide is highly conserved, but in silico tools were inconclusive in predicting an effect on splicing. (SP) 0600 - Variant is located in the annotated ROD2 domain (PMID: 32112656). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been previously reported several times as a VUS, where one individual was reported to have HCM (LOVD, ClinVar). It has also been observed once each in an individual with frontotemporal dementia, and the control cohort (PMID: 26555887). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Oct 31, 2018

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2023

The p.W1766R variant (also known as c.5296T>C), located in coding exon 31 of the FLNC gene, results from a T to C substitution at nucleotide position 5296. The tryptophan at codon 1766 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in a subject with frontotemporal dementia as well as in a control subject (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). This alteration was also reported in a hypertrophic cardiomyopathy (HCM) cohort (Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1766 of the FLNC protein (p.Trp1766Arg). This variant is present in population databases (rs751650734, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). ClinVar contains an entry for this variant (Variation ID: 472101). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Primary familial hypertrophic cardiomyopathy;C1836050:Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 08-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Uncertain

0.060

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.51

Sift

Benign

0.26

Sift4G

Benign

0.21

Polyphen

0.0090

Vest4

0.83

MutPred

0.32

Gain of solvent accessibility (P = 0.0133);

MVP

0.93

MPC

0.49

ClinPred

0.14

GERP RS

5.1

Varity_R

0.40

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.47

SpliceAI score (max)

0.040

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