chr17-82563392-C-T

Position:

• chr17-82563392-C-T

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXK2	NM_004514.4	c.458C>T	p.Thr153Met	missense_variant	2/9	ENST00000335255.10
FOXK2	XM_047435919.1	c.458C>T	p.Thr153Met	missense_variant	2/9
FOXK2	XM_047435920.1	c.458C>T	p.Thr153Met	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXK2	ENST00000335255.10	c.458C>T	p.Thr153Met	missense_variant	2/9	1	NM_004514.4	P1

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

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

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

Jul 11, 2022

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;.
MutationTaster	Benign	1.0	D
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

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: rs866802169; hg19: chr17-80521268;