rs559639511

chr7-128852937-C-Gchr7-128852937-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001458.5(FLNC):c.6114C>G(p.Ile2038Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I2038L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.66

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNC

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.6114C>G	p.Ile2038Met	missense_variant	37/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.215+348G>C		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.6015C>G	p.Ile2005Met	missense_variant	36/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.6114C>G	p.Ile2038Met	missense_variant	37/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.6015C>G	p.Ile2005Met	missense_variant	36/47	1		A1
FLNC-AS1	ENST00000469965.1	n.215+348G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2021

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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 2038 of the FLNC protein (p.Ile2038Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. 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	0.26
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.20	N
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.055	T;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.42		Gain of ubiquitination at K2043 (P = 0.0509);.;
MVP		0.75
MPC		1.8
ClinPred		0.79	D
GERP RS		-3.1
Varity_R		0.25
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128492991;