7-128857283-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001458.5(FLNC):​c.7727A>C​(p.Lys2576Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. K2576N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

FLNC
NM_001458.5 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.34
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-AS1 (HGNC:53474): (FLNC antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FLNCNM_001458.5 linkuse as main transcriptc.7727A>C p.Lys2576Thr missense_variant 46/48 ENST00000325888.13
FLNC-AS1NR_149055.1 linkuse as main transcriptn.103-3886T>G intron_variant, non_coding_transcript_variant
FLNCNM_001127487.2 linkuse as main transcriptc.7628A>C p.Lys2543Thr missense_variant 45/47

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FLNCENST00000325888.13 linkuse as main transcriptc.7727A>C p.Lys2576Thr missense_variant 46/481 NM_001458.5 P3Q14315-1
FLNCENST00000346177.6 linkuse as main transcriptc.7628A>C p.Lys2543Thr missense_variant 45/471 A1Q14315-2
FLNC-AS1ENST00000469965.1 linkuse as main transcriptn.103-3886T>G 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
LINK: link

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 submitterclinical testingInvitaeNov 19, 2017Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with FLNC-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with threonine at codon 2576 of the FLNC protein (p.Lys2576Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Uncertain
0.51
D
MutationAssessor
Uncertain
2.5
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-4.8
D;D
REVEL
Pathogenic
0.85
Sift
Benign
0.034
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.78
MutPred
0.70
Loss of methylation at K2576 (P = 0.0099);.;
MVP
0.88
MPC
1.9
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.60
gMVP
0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554401912; hg19: chr7-128497337; API