Genetic Variant NM_001458.5:c.5275C>A (chr7-128850051-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001458.5(FLNC):c.5275C>A(p.Pro1759Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1759S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.916

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 links:

FLNC-AS1 (HGNC:53474): (FLNC antisense RNA 1)

FLNC-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17859176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FLNC	NM_001458.5 link	c.5275C>A	p.Pro1759Thr	missense_variant	Exon 31 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 link	c.5200-333C>A		intron_variant	Intron 30 of 46		NP_001120959.1
FLNC-AS1	NR_149055.1 link	n.*111G>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.5275C>A	p.Pro1759Thr	missense_variant	Exon 31 of 48	1	NM_001458.5	ENSP00000327145.8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1391266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31884

American (AMR)

AF:

0.00

AC:

AN:

36244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25212

East Asian (EAS)

AF:

0.00

AC:

AN:

36142

South Asian (SAS)

AF:

0.00

AC:

AN:

79664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1081830

Other (OTH)

AF:

0.00

AC:

AN:

58160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

0.00042

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.47

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.0

PhyloP100

0.92

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.62

REVEL

Benign

0.22

Sift

Benign

0.15

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.46

MutPred

0.25

Gain of phosphorylation at P1759 (P = 0.0041);

MVP

0.53

MPC

0.31

ClinPred

0.15

GERP RS

5.1

Varity_R

0.059

gMVP

0.33

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over