rs1554401209

Positions:

• chr7-128854028-G-A
• chr7-128854028-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_001458.5(FLNC):​c.6539G>A​(p.Arg2180His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.74

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-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19304842).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.6539G>A	p.Arg2180His	missense_variant	40/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.6440G>A	p.Arg2147His	missense_variant	39/47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.103-631C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.6539G>A	p.Arg2180His	missense_variant	40/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.6440G>A	p.Arg2147His	missense_variant	39/47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.103-631C>T		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460724 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 726682

Gnomad4 AFR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The p.R2180H variant (also known as c.6539G>A), located in coding exon 40 of the FLNC gene, results from a G to A substitution at nucleotide position 6539. The arginine at codon 2180 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a pediatric dilated cardiomyopathy cohort (Khan RS et al. J Am Heart Assoc, 2022 01;11:e022854). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FLNC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 2180 of the FLNC protein (p.Arg2180His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.0080	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Benign	0.87
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.82	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.72	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.014	B;B
Vest4		0.27
MutPred		0.32		Loss of MoRF binding (P = 0.0152);.;
MVP		0.52
MPC		0.86
ClinPred		0.61	D
GERP RS		5.6
Varity_R		0.078
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1554401209; hg19: chr7-128494082; COSMIC: COSV100369104;