rs387906586

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The ENST00000325888.13(FLNC):​c.752T>C​(p.Met251Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M251V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

FLNC
ENST00000325888.13 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.02
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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, 0.937
PP5
Variant 7-128837450-T-C is Pathogenic according to our data. Variant chr7-128837450-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128837450-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FLNCNM_001458.5 linkuse as main transcriptc.752T>C p.Met251Thr missense_variant 4/48 ENST00000325888.13 NP_001449.3
FLNCNM_001127487.2 linkuse as main transcriptc.752T>C p.Met251Thr missense_variant 4/47 NP_001120959.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkuse as main transcriptc.752T>C p.Met251Thr missense_variant 4/481 NM_001458.5 ENSP00000327145 P3Q14315-1
FLNCENST00000346177.6 linkuse as main transcriptc.752T>C p.Met251Thr missense_variant 4/471 ENSP00000344002 A1Q14315-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 22, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024FLNC: PP4:Strong, PM2, PP1, PP3, PS3:Supporting, PS4:Supporting -
Distal myopathy with posterior leg and anterior hand involvement Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 10, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
D;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.69
Gain of glycosylation at M251 (P = 0.0154);Gain of glycosylation at M251 (P = 0.0154);
MVP
0.97
MPC
2.3
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.97

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: rs387906586; hg19: chr7-128477504; API