chr6-1611782-A-ACGG

Variant names:

• chr6-1611782-A-ACGG
• rs398123612
• NM_001453.3:c.1359_1361dupCGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001453.3(FOXC1):​c.1359_1361dupCGG​(p.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 0.238 in 1,439,242 control chromosomes in the GnomAD database, including 27,814 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G454G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (5705 hom., cov: 19)
  • Exomes 𝑓: 0.23 (22109 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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-ACGG is Benign according to our data. Variant chr6-1611782-A-ACGG is described in ClinVar as Benign. ClinVar VariationId is 93747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

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.1359_1361dupCGG	p.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.1359_1361dupCGG	p.Gly454dup	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes AF: 0.283 AC: 40439 AN: 142866 Hom.: 5695 Cov.: 19

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.240 AC: 15558 AN: 64810 AF XY: 0.235

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.315

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.233 AC: 301476 AN: 1296298 Hom.: 22109 Cov.: 33 AF XY: 0.231 AC XY: 147705 AN XY: 639150

African (AFR) AF: 0.284 AC: 7341 AN: 25830

American (AMR) AF: 0.306 AC: 7257 AN: 23736

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 4411 AN: 22490

East Asian (EAS) AF: 0.367 AC: 10369 AN: 28230

South Asian (SAS) AF: 0.245 AC: 16906 AN: 68982

European-Finnish (FIN) AF: 0.197 AC: 6542 AN: 33200

Middle Eastern (MID) AF: 0.184 AC: 876 AN: 4772

European-Non Finnish (NFE) AF: 0.227 AC: 234659 AN: 1035480

Other (OTH) AF: 0.245 AC: 13115 AN: 53578

GnomAD4 genome AF: 0.283 AC: 40485 AN: 142944 Hom.: 5705 Cov.: 19 AF XY: 0.284 AC XY: 19767 AN XY: 69530

African (AFR) AF: 0.327 AC: 12659 AN: 38666

American (AMR) AF: 0.338 AC: 4949 AN: 14646

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 727 AN: 3336

East Asian (EAS) AF: 0.415 AC: 1952 AN: 4706

South Asian (SAS) AF: 0.333 AC: 1475 AN: 4436

European-Finnish (FIN) AF: 0.225 AC: 2103 AN: 9340

Middle Eastern (MID) AF: 0.169 AC: 43 AN: 254

European-Non Finnish (NFE) AF: 0.245 AC: 15886 AN: 64736

Other (OTH) AF: 0.276 AC: 547 AN: 1982

Alfa AF: 0.0839 Hom.: 98

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Axenfeld-Rieger syndrome type 3 (2)
-	-	2	not specified (2)
-	-	1	Anterior segment dysgenesis 3 (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV66515836;