17-82520186-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004514.4(FOXK2):c.298C>T(p.Pro100Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20884949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXK2	NM_004514.4	c.298C>T	p.Pro100Ser	missense_variant	1/9	ENST00000335255.10
FOXK2	XM_047435919.1	c.298C>T	p.Pro100Ser	missense_variant	1/9
FOXK2	XM_047435920.1	c.298C>T	p.Pro100Ser	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXK2	ENST00000335255.10	c.298C>T	p.Pro100Ser	missense_variant	1/9	1	NM_004514.4	P1
FOXK2	ENST00000473637.6	c.298C>T	p.Pro100Ser	missense_variant, NMD_transcript_variant	1/10	1
FOXK2	ENST00000527313.6	n.210C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

May 17, 2023

The c.298C>T (p.P100S) alteration is located in exon 1 (coding exon 1) of the FOXK2 gene. This alteration results from a C to T substitution at nucleotide position 298, causing the proline (P) at amino acid position 100 to be replaced by a serine (S). 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	Benign	0.064
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.16
Sift	Benign	0.79	T
Sift4G	Benign	0.81	T
Polyphen		0.015	B
Vest4		0.17
MutPred		0.30		Loss of catalytic residue at P99 (P = 0.0116);
MVP		0.56
MPC		1.1
ClinPred		0.046	T
GERP RS		0.085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.073
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-80478062;