6-1611782-ACGGCGGCGGCGGCGG-ACGGCGGCGGCGGCGGCGGCGG

Variant names:

• chr6-1611782-A-ACGGCGG
• rs398123612
• NM_001453.3:c.1356_1361dupCGGCGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001453.3(FOXC1):​c.1356_1361dupCGGCGG​(p.Gly453_Gly454dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,440,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G454G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 19)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.613
• Publications: 15 publications found

Genes affected

FOXC1 (HGNC:3800): (forkhead box C1) 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 has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]

FOXC1 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• Axenfeld-Rieger syndrome type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• aniridia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Axenfeld anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated aniridia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Rieger anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-1611782-A-ACGGCGG is Benign according to our data. Variant chr6-1611782-A-ACGGCGG is described in ClinVar as Likely_benign. ClinVar VariationId is 469649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000503 (72/143116) while in subpopulation AMR AF = 0.00184 (27/14668). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001453.3. 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
	FOXC1	NM_001453.3	MANE Select	c.1356_1361dupCGGCGG	p.Gly453_Gly454dup	disruptive_inframe_insertion	Exon 1 of 1	NP_001444.2	W6CJ52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	ENST00000645831.2	MANE Select	c.1356_1361dupCGGCGG	p.Gly453_Gly454dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes AF: 0.000503 AC: 72 AN: 143038 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00169

Gnomad SAS AF: 0.000225

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000123

Gnomad OTH AF: 0.000509

GnomAD2 exomes AF: 0.000247 AC: 16 AN: 64810 AF XY: 0.000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000451

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.000187 AC: 243 AN: 1297664 Hom.: 0 Cov.: 33 AF XY: 0.000163 AC XY: 104 AN XY: 639916

African (AFR) AF: 0.000813 AC: 21 AN: 25842

American (AMR) AF: 0.000713 AC: 17 AN: 23832

Ashkenazi Jewish (ASJ) AF: 0.0000887 AC: 2 AN: 22552

East Asian (EAS) AF: 0.000601 AC: 17 AN: 28298

South Asian (SAS) AF: 0.0000865 AC: 6 AN: 69336

European-Finnish (FIN) AF: 0.0000301 AC: 1 AN: 33252

Middle Eastern (MID) AF: 0.00126 AC: 6 AN: 4778

European-Non Finnish (NFE) AF: 0.000145 AC: 150 AN: 1036136

Other (OTH) AF: 0.000429 AC: 23 AN: 53638

GnomAD4 genome AF: 0.000503 AC: 72 AN: 143116 Hom.: 0 Cov.: 19 AF XY: 0.000560 AC XY: 39 AN XY: 69632

African (AFR) AF: 0.000697 AC: 27 AN: 38710

American (AMR) AF: 0.00184 AC: 27 AN: 14668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3340

East Asian (EAS) AF: 0.00170 AC: 8 AN: 4712

South Asian (SAS) AF: 0.000225 AC: 1 AN: 4438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.000123 AC: 8 AN: 64808

Other (OTH) AF: 0.000505 AC: 1 AN: 1982

Alfa AF: 0.00 Hom.: 98

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Axenfeld-Rieger syndrome type 3 (1)
-	-	1	FOXC1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs398123612; hg19: chr6-1612017;