NM_005251.3:c.19G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005251.3(FOXC2):​c.19G>A​(p.Val7Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,700 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 (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FOXC2
NM_005251.3 missense

Scores

6
10
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34
Variant links:
Genes affected
FOXC2 (HGNC:3801): (forkhead box C2) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the development of mesenchymal tissues. [provided by RefSeq, Jul 2008]
FOXC2-AS1 (HGNC:50665): (FOXC2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXC2NM_005251.3 linkc.19G>A p.Val7Met missense_variant Exon 1 of 1 ENST00000649859.1 NP_005242.1 Q99958
FOXC2-AS1NR_125795.1 linkn.145+263C>T intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXC2ENST00000649859.1 linkc.19G>A p.Val7Met missense_variant Exon 1 of 1 NM_005251.3 ENSP00000497759.1 Q99958
FOXC2-AS1ENST00000563280.3 linkn.231+263C>T intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460700
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726680
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Sep 21, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This missense change has been observed in individual(s) with FOXC2-related conditions (PMID: 30029678). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 7 of the FOXC2 protein (p.Val7Met). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;D
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Benign
2.0
M;M
PrimateAI
Pathogenic
0.94
D
PROVEAN
Benign
-2.2
.;N
REVEL
Uncertain
0.51
Sift
Uncertain
0.0010
.;D
Sift4G
Uncertain
0.014
.;D
Polyphen
1.0
D;D
Vest4
0.53
MutPred
0.21
Gain of disorder (P = 0.05);Gain of disorder (P = 0.05);
MVP
0.97
ClinPred
0.97
D
GERP RS
3.5
Varity_R
0.26
gMVP
0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1378523304; hg19: chr16-86600960; COSMIC: COSV100234076; API