7-128850048-C-G

Variant names:

• chr7-128850048-C-G
• rs369187211
• NM_001458.5:c.5272C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001458.5(FLNC):​c.5272C>G​(p.Arg1758Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1758Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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:53474): (FLNC antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20136663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.5272C>G	p.Arg1758Gly	missense_variant	Exon 31 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.5200-336C>G		intron_variant	Intron 30 of 46		NP_001120959.1
FLNC-AS1	NR_149055.1	n.*114G>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.5272C>G	p.Arg1758Gly	missense_variant	Exon 31 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.5200-336C>G		intron_variant	Intron 30 of 46	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.*114G>C		downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1393630 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 688758

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Uncertain:1

Aug 06, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glycine at codon 1758 of the FLNC protein (p.Arg1758Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLNC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.24	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.24
Sift	Benign	0.36	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.39
MutPred		0.31		Loss of solvent accessibility (P = 0.0044);
MVP		0.57
MPC		0.35
ClinPred		0.20	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.35

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: rs369187211; hg19: chr7-128490102;