17-82519947-C-T

Variant names:

• chr17-82519947-C-T
• rs1045659439
• NM_004514.4:c.59C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004514.4(FOXK2):​c.59C>T​(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 827,540 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 27)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03664574).
• BS2: High AC in GnomAd4 at 303 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4	c.59C>T	p.Ala20Val	missense_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.59C>T	p.Ala20Val	missense_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1	c.59C>T	p.Ala20Val	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.59C>T	p.Ala20Val	missense_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5
FOXK2	ENST00000473637.6	n.59C>T		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2
FOXK2	ENST00000527313.6	n.-30C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 303 AN: 122542 Hom.: 3 Cov.: 27

Gnomad AFR AF: 0.00832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000184

Gnomad OTH AF: 0.00187

GnomAD4 exome AF: 0.000228 AC: 161 AN: 704982 Hom.: 0 Cov.: 7 AF XY: 0.000211 AC XY: 69 AN XY: 326508

African (AFR) AF: 0.0109 AC: 149 AN: 13608

American (AMR) AF: 0.00 AC: 0 AN: 968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4640

East Asian (EAS) AF: 0.00 AC: 0 AN: 4082

South Asian (SAS) AF: 0.0000645 AC: 1 AN: 15506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1372

European-Non Finnish (NFE) AF: 0.00000156 AC: 1 AN: 640318

Other (OTH) AF: 0.000428 AC: 10 AN: 23354

GnomAD4 genome AF: 0.00247 AC: 303 AN: 122558 Hom.: 3 Cov.: 27 AF XY: 0.00239 AC XY: 143 AN XY: 59808

African (AFR) AF: 0.00831 AC: 290 AN: 34918

American (AMR) AF: 0.000687 AC: 8 AN: 11646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2930

East Asian (EAS) AF: 0.00 AC: 0 AN: 4604

South Asian (SAS) AF: 0.000235 AC: 1 AN: 4250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000184 AC: 1 AN: 54414

Other (OTH) AF: 0.00185 AC: 3 AN: 1620

Alfa AF: 0.00214 Hom.: 0

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.59C>T (p.A20V) 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 59, causing the alanine (A) at amino acid position 20 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.20	N
PhyloP100		2.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.39	T
Polyphen		0.24	B
Vest4		0.11
MutPred		0.23		Loss of glycosylation at P15 (P = 0.1234);
MVP		0.71
MPC		1.1
ClinPred		0.24	T
GERP RS		0.57
PromoterAI		-0.037	Neutral
Varity_R		0.044
gMVP		0.21
Mutation Taster		=97/3	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: rs1045659439; hg19: chr17-80477823;