rs147258453

Variant names:

• chr16-86568666-A-G
• rs147258453
• NM_005251.3:c.1331A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_005251.3(FOXC2):​c.1331A>G​(p.Gln444Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,612,680 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: FOXC2 NM_005251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10794449).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00128 (194/152124) while in subpopulation NFE AF = 0.00235 (160/67968). AF 95% confidence interval is 0.00206. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC2	NM_005251.3	c.1331A>G	p.Gln444Arg	missense_variant	Exon 1 of 1	ENST00000649859.1	NP_005242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC2	ENST00000649859.1	c.1331A>G	p.Gln444Arg	missense_variant	Exon 1 of 1		NM_005251.3	ENSP00000497759.1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152008 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00115 AC: 284 AN: 246900 AF XY: 0.00109

Gnomad AFR exome AF: 0.000325

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00208 AC: 3045 AN: 1460556 Hom.: 4 Cov.: 32 AF XY: 0.00198 AC XY: 1437 AN XY: 726566

Gnomad4 AFR exome AF: 0.000418 AC: 14 AN: 33480

Gnomad4 AMR exome AF: 0.00134 AC: 60 AN: 44724

Gnomad4 ASJ exome AF: 0.0000765 AC: 2 AN: 26136

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39696

Gnomad4 SAS exome AF: 0.000267 AC: 23 AN: 86258

Gnomad4 FIN exome AF: 0.0000767 AC: 4 AN: 52130

Gnomad4 NFE exome AF: 0.00255 AC: 2832 AN: 1111980

Gnomad4 Remaining exome AF: 0.00177 AC: 107 AN: 60384

GnomAD4 genome AF: 0.00128 AC: 194 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74396

Gnomad4 AFR AF: 0.000313 AC: 0.000312997 AN: 0.000312997

Gnomad4 AMR AF: 0.00105 AC: 0.00104616 AN: 0.00104616

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000194 AC: 0.000193874 AN: 0.000193874

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000946 AC: 0.0000946074 AN: 0.0000946074

Gnomad4 NFE AF: 0.00235 AC: 0.00235405 AN: 0.00235405

Gnomad4 OTH AF: 0.00142 AC: 0.00142315 AN: 0.00142315

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00106 AC: 129

EpiCase AF: 0.00196

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXC2: BS1, BS2 -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Distichiasis-lymphedema syndrome Uncertain:1

Apr 03, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	.;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.015	.;D
Sift4G	Benign	0.084	.;T
Polyphen		0.98	D;D
Vest4		0.79
MVP		0.85
ClinPred		0.053	T
GERP RS		4.3
Varity_R		0.30
gMVP		0.48
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs147258453; hg19: chr16-86602272; COSMIC: COSV99076753; COSMIC: COSV99076753;