rs866802169

Variant names:

• chr17-82563392-C-T
• rs866802169
• NM_004514.4:c.458C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004514.4(FOXK2):​c.458C>T​(p.Thr153Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4	c.458C>T	p.Thr153Met	missense_variant	Exon 2 of 9	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.458C>T	p.Thr153Met	missense_variant	Exon 2 of 9		XP_047291875.1
FOXK2	XM_047435920.1	c.458C>T	p.Thr153Met	missense_variant	Exon 2 of 5		XP_047291876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXK2	ENST00000335255.10	c.458C>T	p.Thr153Met	missense_variant	Exon 2 of 9	1	NM_004514.4	ENSP00000335677.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.458C>T (p.T153M) alteration is located in exon 2 (coding exon 2) of the FOXK2 gene. This alteration results from a C to T substitution at nucleotide position 458, causing the threonine (T) at amino acid position 153 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T;T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.8	L;.
PhyloP100		4.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.52
Sift	Benign	0.26	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.15	B;.
Vest4		0.82
MutPred		0.54		Gain of ubiquitination at K151 (P = 0.0497);.;
MVP		0.69
MPC		2.3
ClinPred		0.80	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.51
Mutation Taster		=47/53	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

Other links and lift over

dbSNP: rs866802169; hg19: chr17-80521268;