16-86567463-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005251.3(FOXC2):c.130del(p.His44ThrfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXC2 NM_005251.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.97

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 56 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-86567463-GC-G is Pathogenic according to our data. Variant chr16-86567463-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 449991.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXC2	NM_005251.3	c.130del	p.His44ThrfsTer28	frameshift_variant	1/1	ENST00000649859.1
FOXC2-AS1	NR_125795.1	n.145+153del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXC2	ENST00000649859.1	c.130del	p.His44ThrfsTer28	frameshift_variant	1/1		NM_005251.3	P1
FOXC2-AS1	ENST00000563280.3	n.231+153del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2017

The c.130delC variant in the FOXC2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Histidine 44, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.His44Thrfs28. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 458 amino acids are replaced with 27 incorrect residues. The c.130delC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.130delC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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: rs1555531276; hg19: chr16-86601069;