dbSNP rs138318843: FOXC2:p.Ser36Ser (chr16-86567443-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005251.3(FOXC2):c.108C>T(p.Ser36Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,613,278 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 68 hom. )

Consequence

FOXC2
NM_005251.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.521

Publications

3 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 16-86567443-C-T is Benign according to our data. Variant chr16-86567443-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.521 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0064 (975/152290) while in subpopulation NFE AF = 0.00987 (671/68016). AF 95% confidence interval is 0.00925. There are 4 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 975 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC2	NM_005251.3	MANE Select	c.108C>T	p.Ser36Ser	synonymous	Exon 1 of 1	NP_005242.1	Q99958
	FOXC2-AS1	NR_125795.1		n.145+174G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXC2	ENST00000649859.1	MANE Select	c.108C>T	p.Ser36Ser	synonymous	Exon 1 of 1	ENSP00000497759.1	Q99958
FOXC2-AS1	ENST00000809049.1		n.247G>A		non_coding_transcript_exon	Exon 1 of 2
FOXC2-AS1	ENST00000563280.4	TSL:3	n.313+174G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00641

AC:

975

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00986

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00678

AC:

1694

AN:

249682

AF XY:

0.00715

show subpopulations

Gnomad AFR exome

AF:

0.00195

Gnomad AMR exome

AF:

0.00530

Gnomad ASJ exome

AF:

0.00220

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00852

GnomAD4 exome

AF:

0.00807

AC:

11796

AN:

1460988

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

5717

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33476

American (AMR)

AF:

0.00564

AC:

252

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00218

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00238

AC:

205

AN:

86238

European-Finnish (FIN)

AF:

0.00269

AC:

142

AN:

52726

Middle Eastern (MID)

AF:

0.0260

AC:

150

AN:

5768

European-Non Finnish (NFE)

AF:

0.00942

AC:

10470

AN:

1111900

Other (OTH)

AF:

0.00740

AC:

447

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

770

1539

2309

3078

3848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.00640

AC:

975

AN:

152290

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41574

American (AMR)

AF:

0.00771

AC:

118

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00987

AC:

671

AN:

68016

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00833

Hom.:

Bravo

AF:

0.00726

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0134

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.52

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over