17-82571860-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_004514.4(FOXK2):c.899A>G(p.Lys300Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,407,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.03

Genes affected

FOXK2 (HGNC:6036): (forkhead box K2) The protein encoded by this gene contains a fork head DNA binding domain. This protein can bind to the purine-rich motifs of the HIV long terminal repeat (LTR), and to the similar purine-rich motif in the interleukin 2 (IL2) promoter. It may be involved in the regulation of viral and cellular promoter elements. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a mutagenesis_site Decreases DNA-binding to 20%. (size 0) in uniprot entity FOXK2_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXK2	NM_004514.4	c.899A>G	p.Lys300Arg	missense_variant	4/9	ENST00000335255.10
FOXK2	XM_047435919.1	c.899A>G	p.Lys300Arg	missense_variant	4/9
FOXK2	XM_047435920.1	c.899A>G	p.Lys300Arg	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXK2	ENST00000335255.10	c.899A>G	p.Lys300Arg	missense_variant	4/9	1	NM_004514.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000497 AC: 7 AN: 1407954 Hom.: 0 Cov.: 30 AF XY: 0.00000572 AC XY: 4 AN XY: 698718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000458

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.899A>G (p.K300R) alteration is located in exon 4 (coding exon 4) of the FOXK2 gene. This alteration results from a A to G substitution at nucleotide position 899, causing the lysine (K) at amino acid position 300 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.011	D;D;T
Sift4G	Uncertain	0.040	D;T;T
Polyphen		1.0	D;.;.
Vest4		0.58
MutPred		0.40		Loss of methylation at K300 (P = 0.011);.;.;
MVP		0.89
MPC		2.0
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1052477828; hg19: chr17-80529736;