rs150986092

chr7-128850054-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_001458.5(FLNC):c.5278G>A(p.Gly1760Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,542,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1760D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.0170

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNC
• BP4: Computational evidence support a benign effect (MetaRNN=0.006872475).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000112 (17/152248) while in subpopulation EAS AF= 0.00155 (8/5178). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.5278G>A	p.Gly1760Ser	missense_variant	31/48	ENST00000325888.13
FLNC	NM_001127487.2	c.5200-330G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.5278G>A	p.Gly1760Ser	missense_variant	31/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.5200-330G>A		intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000186 AC: 27 AN: 145052 Hom.: 0 AF XY: 0.000216 AC XY: 17 AN XY: 78582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000802

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000724

Gnomad SAS exome AF: 0.000608

Gnomad FIN exome AF: 0.000145

Gnomad NFE exome AF: 0.0000341

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 142 AN: 1390544 Hom.: 0 Cov.: 32 AF XY: 0.000131 AC XY: 90 AN XY: 686996

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.0000276

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000969

Gnomad4 SAS exome AF: 0.000779

Gnomad4 FIN exome AF: 0.000220

Gnomad4 NFE exome AF: 0.0000157

Gnomad4 OTH exome AF: 0.000275

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74436

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000106 AC: 12

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2020	Reported in a patient with limb-girdle muscular dystrophy and a patient with HCM (Yu et al., 2017; Cui et al., 2018); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 472098; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30411535, 28403181) -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

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

Dec 15, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1760 of the FLNC protein (p.Gly1760Ser). This variant is present in population databases (rs150986092, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with FLNC-related conditions (PMID: 28403181, 30411535, 30418145, 33250842). ClinVar contains an entry for this variant (Variation ID: 472098). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2019

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	8.6
Dann	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.36
MPC		0.28
ClinPred		0.011	T
GERP RS		-1.2
Varity_R		0.025
gMVP		0.28

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

Other links and lift over

dbSNP: rs150986092; hg19: chr7-128490108;