rs530742766
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001458.5(FLNC):āc.3506A>Gā(p.Lys1169Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,613,804 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.00039 ( 0 hom., cov: 33)
Exomes š: 0.00061 ( 13 hom. )
Consequence
FLNC
NM_001458.5 missense
NM_001458.5 missense
Scores
8
10
Clinical Significance
Conservation
PhyloP100: 2.62
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.0091686845).
BP6
Variant 7-128844971-A-G is Benign according to our data. Variant chr7-128844971-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 290008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128844971-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000387 (59/152338) while in subpopulation SAS AF= 0.012 (58/4832). AF 95% confidence interval is 0.00953. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 59 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.3506A>G | p.Lys1169Arg | missense_variant | 21/48 | ENST00000325888.13 | NP_001449.3 | |
FLNC | NM_001127487.2 | c.3506A>G | p.Lys1169Arg | missense_variant | 21/47 | NP_001120959.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.3506A>G | p.Lys1169Arg | missense_variant | 21/48 | 1 | NM_001458.5 | ENSP00000327145.8 | ||
FLNC | ENST00000346177.6 | c.3506A>G | p.Lys1169Arg | missense_variant | 21/47 | 1 | ENSP00000344002.6 |
Frequencies
GnomAD3 genomes AF: 0.000381 AC: 58AN: 152220Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
58
AN:
152220
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00113 AC: 282AN: 249180Hom.: 2 AF XY: 0.00160 AC XY: 216AN XY: 135274
GnomAD3 exomes
AF:
AC:
282
AN:
249180
Hom.:
AF XY:
AC XY:
216
AN XY:
135274
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000610 AC: 891AN: 1461466Hom.: 13 Cov.: 34 AF XY: 0.000917 AC XY: 667AN XY: 727042
GnomAD4 exome
AF:
AC:
891
AN:
1461466
Hom.:
Cov.:
34
AF XY:
AC XY:
667
AN XY:
727042
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000387 AC: 59AN: 152338Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42AN XY: 74484
GnomAD4 genome
AF:
AC:
59
AN:
152338
Hom.:
Cov.:
33
AF XY:
AC XY:
42
AN XY:
74484
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
166
Asia WGS
AF:
AC:
16
AN:
3478
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 05, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at