rs199804244

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001458.5(FLNC):​c.3938G>A​(p.Arg1313Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1313P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

4
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.03

Publications

1 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 Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
  • myofibrillar myopathy 5
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
  • hypertrophic cardiomyopathy 26
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
  • distal myopathy with posterior leg and anterior hand involvement
    Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
  • familial isolated restrictive cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • heart conduction disease
    Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6
Variant 7-128846137-G-A is Benign according to our data. Variant chr7-128846137-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472052.
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000362 (55/152132) while in subpopulation AMR AF = 0.00111 (17/15286). AF 95% confidence interval is 0.000708. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 55 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FLNC
NM_001458.5
MANE Select
c.3938G>Ap.Arg1313Gln
missense
Exon 22 of 48NP_001449.3
FLNC
NM_001127487.2
c.3938G>Ap.Arg1313Gln
missense
Exon 22 of 47NP_001120959.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FLNC
ENST00000325888.13
TSL:1 MANE Select
c.3938G>Ap.Arg1313Gln
missense
Exon 22 of 48ENSP00000327145.8
FLNC
ENST00000346177.6
TSL:1
c.3938G>Ap.Arg1313Gln
missense
Exon 22 of 47ENSP00000344002.6
FLNC
ENST00000714183.1
c.3938G>Ap.Arg1313Gln
missense
Exon 22 of 47ENSP00000519472.1

Frequencies

GnomAD3 genomes
AF:
0.000362
AC:
55
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000529
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000205
AC:
51
AN:
249112
AF XY:
0.000222
show subpopulations
Gnomad AFR exome
AF:
0.0000647
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000398
Gnomad OTH exome
AF:
0.000496
GnomAD4 exome
AF:
0.000414
AC:
605
AN:
1461776
Hom.:
0
Cov.:
34
AF XY:
0.000419
AC XY:
305
AN XY:
727198
show subpopulations
African (AFR)
AF:
0.000149
AC:
5
AN:
33480
American (AMR)
AF:
0.0000671
AC:
3
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53356
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.000523
AC:
582
AN:
1111976
Other (OTH)
AF:
0.000232
AC:
14
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.468
Heterozygous variant carriers
0
34
68
103
137
171
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
22
44
66
88
110
<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
AF:
0.000362
AC:
55
AN:
152132
Hom.:
0
Cov.:
32
AF XY:
0.000431
AC XY:
32
AN XY:
74314
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41424
American (AMR)
AF:
0.00111
AC:
17
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000529
AC:
36
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000319
Hom.:
0
Bravo
AF:
0.000348
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.000382
EpiControl
AF:
0.000533

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
2
-
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 (2)
-
-
2
not specified (2)
-
1
-
Cardiovascular phenotype (1)
-
-
1
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant (1)
-
-
1
not provided (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
27
DANN
Benign
0.96
DEOGEN2
Benign
0.31
T
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.053
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
1.1
L
PhyloP100
2.0
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.39
N
REVEL
Uncertain
0.41
Sift
Benign
0.81
T
Sift4G
Benign
0.53
T
Polyphen
0.016
B
Vest4
0.56
MVP
0.70
MPC
0.64
ClinPred
0.033
T
GERP RS
5.1
Varity_R
0.041
gMVP
0.50
Mutation Taster
=87/13
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.22
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs199804244; hg19: chr7-128486191; COSMIC: COSV106095756; COSMIC: COSV106095756; API