rs41312258

chr16-86567761-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005251.3(FOXC2):c.426G>A(p.Lys142=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,614,176 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (32 hom.)
• Consequence: FOXC2 NM_005251.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.19

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

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 16-86567761-G-A is Benign according to our data. Variant chr16-86567761-G-A is described in ClinVar as [Benign]. Clinvar id is 707267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00291 (443/152320) while in subpopulation SAS AF= 0.0191 (92/4822). AF 95% confidence interval is 0.0159. There are 2 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC2	NM_005251.3	c.426G>A	p.Lys142=	synonymous_variant	1/1	ENST00000649859.1
FOXC2-AS1	NR_125795.1	n.1C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC2	ENST00000649859.1	c.426G>A	p.Lys142=	synonymous_variant	1/1		NM_005251.3	P1
FOXC2-AS1	ENST00000563280.3	n.87C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152202 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00416 AC: 1046 AN: 251420 Hom.: 10 AF XY: 0.00489 AC XY: 665 AN XY: 135904

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00436 AC: 6380 AN: 1461856 Hom.: 32 Cov.: 32 AF XY: 0.00469 AC XY: 3409 AN XY: 727222

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0162

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00291 AC: 443 AN: 152320 Hom.: 2 Cov.: 33 AF XY: 0.00293 AC XY: 218 AN XY: 74478

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00308 Hom.: 1

Bravo AF: 0.00223

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00462

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.97

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: rs41312258; hg19: chr16-86601367; COSMIC: COSV105203893;