17-82519932-C-T

Variant names:

• chr17-82519932-C-T
• rs1465335181
• NM_004514.4:c.44C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004514.4(FOXK2):​c.44C>T​(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000919 in 978,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.145
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.109971434).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 5		XP_047291876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXK2	ENST00000335255.10	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5
FOXK2	ENST00000473637.6	n.44C>T		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2
FOXK2	ENST00000527313.6	n.-45C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 145180 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000840 AC: 7 AN: 833742 Hom.: 0 Cov.: 28 AF XY: 0.0000130 AC XY: 5 AN XY: 385082

African (AFR) AF: 0.00 AC: 0 AN: 15772

American (AMR) AF: 0.00 AC: 0 AN: 1000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5154

East Asian (EAS) AF: 0.00 AC: 0 AN: 3632

South Asian (SAS) AF: 0.00 AC: 0 AN: 17070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1624

European-Non Finnish (NFE) AF: 0.00000919 AC: 7 AN: 761878

Other (OTH) AF: 0.00 AC: 0 AN: 27318

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 145196 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 70638

African (AFR) AF: 0.0000246 AC: 1 AN: 40648

American (AMR) AF: 0.00 AC: 0 AN: 14674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4976

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65394

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44C>T (p.P15L) 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 44, causing the proline (P) at amino acid position 15 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.14
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Uncertain	0.026	D
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.12		Loss of glycosylation at P15 (P = 0.0297);
MVP		0.56
MPC		1.2
ClinPred		0.30	T
GERP RS		2.6
PromoterAI		0.0021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.053
gMVP		0.33
Mutation Taster		=98/2	polymorphism

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: rs1465335181; hg19: chr17-80477808;