chr7-128850853-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001458.5(FLNC):​c.5449A>C​(p.Asn1817His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,612 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 ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1817Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

9
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

Publications

0 publications found
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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.5449A>C p.Asn1817His missense_variant Exon 33 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.5350A>C p.Asn1784His missense_variant Exon 32 of 47 NP_001120959.1 Q14315-2Q59H94
FLNC-AS1NR_149055.1 linkn.316-448T>G intron_variant Intron 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.5449A>C p.Asn1817His missense_variant Exon 33 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461612
Hom.:
0
Cov.:
34
AF XY:
0.00000413
AC XY:
3
AN XY:
727124
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53184
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111974
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Mar 26, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.N1817H variant (also known as c.5449A>C), located in coding exon 33 of the FLNC gene, results from an A to C substitution at nucleotide position 5449. The asparagine at codon 1817 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
0.67
D
MutationAssessor
Uncertain
2.4
M;.
PhyloP100
9.3
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.013
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.86
MutPred
0.50
Loss of sheet (P = 0.0104);.;
MVP
0.89
MPC
1.8
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.53
gMVP
0.88
Mutation Taster
=56/44
polymorphism

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

Other links and lift over

dbSNP: rs373146637; hg19: chr7-128490907; API