Genetic Variant FOXC2:p.Pro410_Thr411insGlnPro (chr16-86568550-T-TCCCCAG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005251.3(FOXC2):c.1224_1229dupCCAGCC(p.Pro410_Thr411insGlnPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,328,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FOXC2
NM_005251.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.145

Publications

0 publications found

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 links:

FOXC2-AS1 (HGNC:50665): (FOXC2 antisense RNA 1)

FOXC2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC2	NM_005251.3 link	c.1224_1229dupCCAGCC	p.Pro410_Thr411insGlnPro	disruptive_inframe_insertion	Exon 1 of 1	ENST00000649859.1	NP_005242.1	Q99958

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC2	ENST00000649859.1 link	c.1224_1229dupCCAGCC	p.Pro410_Thr411insGlnPro	disruptive_inframe_insertion	Exon 1 of 1		NM_005251.3	ENSP00000497759.1		Q99958
FOXC2-AS1	ENST00000809048.1 link	n.62+402_62+407dupCTGGGG		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

48946

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000340

AC:

AN:

1177870

Hom.:

Cov.:

AF XY:

0.00000174

AC XY:

AN XY:

573150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23534

American (AMR)

AF:

0.00

AC:

AN:

14230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17172

East Asian (EAS)

AF:

0.00

AC:

AN:

26456

South Asian (SAS)

AF:

0.00

AC:

AN:

39288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3954

European-Non Finnish (NFE)

AF:

0.00000412

AC:

AN:

971670

Other (OTH)

AF:

0.00

AC:

AN:

47126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

AF:

0.00000665

AC:

AN:

150264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73374

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000244

AC:

AN:

41050

American (AMR)

AF:

0.00

AC:

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5032

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67458

Other (OTH)

AF:

0.00

AC:

AN:

2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Asia WGS

AF:

0.000291

AC:

AN:

3452

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.14

Mutation Taster

=83/17

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over