7-128854900-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001458.5(FLNC):​c.7123G>C​(p.Val2375Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

8
9
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.88
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.822
PP5
Variant 7-128854900-G-C is Pathogenic according to our data. Variant chr7-128854900-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.7123G>C p.Val2375Leu missense_variant Exon 42 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.7024G>C p.Val2342Leu missense_variant Exon 41 of 47 NP_001120959.1 Q14315-2Q59H94
FLNC-AS1NR_149055.1 linkn.103-1503C>G intron_variant Intron 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.7123G>C p.Val2375Leu missense_variant Exon 42 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1
FLNCENST00000346177.6 linkc.7024G>C p.Val2342Leu missense_variant Exon 41 of 47 1 ENSP00000344002.6 Q14315-2
FLNC-AS1ENST00000469965.1 linkn.103-1503C>G intron_variant Intron 1 of 3 4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461734
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727172
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Pathogenic
2.9
M;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-2.4
N;N
REVEL
Pathogenic
0.74
Sift
Benign
0.14
T;T
Sift4G
Uncertain
0.0080
D;D
Polyphen
0.96
D;D
Vest4
0.61
MutPred
0.75
Gain of catalytic residue at V2375 (P = 0.0794);.;
MVP
0.81
MPC
1.7
ClinPred
0.96
D
GERP RS
5.2
Varity_R
0.59
gMVP
0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128494954; API