17-82520201-C-A

Variant names:

• chr17-82520201-C-A
• rs1254074894
• NM_004514.4:c.313C>A

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.313C>A​(p.Pro105Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,336,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P105A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: FOXK2 NM_004514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• 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=0.2441343).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4	c.313C>A	p.Pro105Thr	missense_variant	Exon 1 of 9	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.313C>A	p.Pro105Thr	missense_variant	Exon 1 of 9		XP_047291875.1
FOXK2	XM_047435920.1	c.313C>A	p.Pro105Thr	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.313C>A	p.Pro105Thr	missense_variant	Exon 1 of 9	1	NM_004514.4	ENSP00000335677.5
FOXK2	ENST00000473637.6	n.313C>A		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000436108.2
FOXK2	ENST00000527313.6	n.225C>A		non_coding_transcript_exon_variant	Exon 1 of 3	3
FOXK2	ENST00000570585.1	n.-93C>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151468 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.0000441 AC: 1 AN: 22690 AF XY: 0.0000776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000759 AC: 9 AN: 1185252 Hom.: 0 Cov.: 33 AF XY: 0.00000695 AC XY: 4 AN XY: 575628

African (AFR) AF: 0.00 AC: 0 AN: 23202

American (AMR) AF: 0.00 AC: 0 AN: 9080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15482

East Asian (EAS) AF: 0.00 AC: 0 AN: 26996

South Asian (SAS) AF: 0.00 AC: 0 AN: 41056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3560

European-Non Finnish (NFE) AF: 0.00000818 AC: 8 AN: 977686

Other (OTH) AF: 0.0000210 AC: 1 AN: 47584

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151468 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73962

African (AFR) AF: 0.0000242 AC: 1 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67700

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.84
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.16
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.088
Sift	Benign	0.40	T
Sift4G	Benign	0.24	T
Polyphen		0.49	P
Vest4		0.17
MutPred		0.40		Gain of phosphorylation at P105 (P = 0.0226);
MVP		0.72
MPC		1.3
ClinPred		0.056	T
GERP RS		1.4
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.14
gMVP		0.26
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1254074894; hg19: chr17-80478077;