chr4-184010535-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020225.3(STOX2):​c.1697C>T​(p.Pro566Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

STOX2
NM_020225.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

Publications

3 publications found
Variant links:
Genes affected
STOX2 (HGNC:25450): (storkhead box 2) This gene encodes a Storkhead-box_winged-helix domain containing protein. This protein is differentially expressed in decidual tissue and may be involved in the susceptibility to pre-eclampsia with fetal growth restriction. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (MetaRNN=0.008972377).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STOX2NM_020225.3 linkc.1697C>T p.Pro566Leu missense_variant Exon 3 of 4 ENST00000308497.9 NP_064610.1 Q9P2F5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STOX2ENST00000308497.9 linkc.1697C>T p.Pro566Leu missense_variant Exon 3 of 4 1 NM_020225.3 ENSP00000311257.4 Q9P2F5-1
STOX2ENST00000513034.3 linkc.518-6554C>T intron_variant Intron 2 of 2 3 ENSP00000422118.3 H0Y8U0
STOX2ENST00000506529.1 linkc.-239C>T upstream_gene_variant 1 ENSP00000426209.1 H0YA59

Frequencies

GnomAD3 genomes
AF:
0.000230
AC:
35
AN:
152232
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000719
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000185
AC:
46
AN:
248414
AF XY:
0.000215
show subpopulations
Gnomad AFR exome
AF:
0.000584
Gnomad AMR exome
AF:
0.000348
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.0000533
Gnomad OTH exome
AF:
0.000332
GnomAD4 exome
AF:
0.000124
AC:
181
AN:
1461526
Hom.:
1
Cov.:
39
AF XY:
0.000136
AC XY:
99
AN XY:
727032
show subpopulations
African (AFR)
AF:
0.000687
AC:
23
AN:
33476
American (AMR)
AF:
0.000492
AC:
22
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.000789
AC:
68
AN:
86226
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53364
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000549
AC:
61
AN:
1111798
Other (OTH)
AF:
0.000116
AC:
7
AN:
60370
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
13
25
38
50
63
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000230
AC:
35
AN:
152350
Hom.:
0
Cov.:
32
AF XY:
0.000255
AC XY:
19
AN XY:
74506
show subpopulations
African (AFR)
AF:
0.000457
AC:
19
AN:
41576
American (AMR)
AF:
0.000718
AC:
11
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.000622
AC:
3
AN:
4826
European-Finnish (FIN)
AF:
0.0000941
AC:
1
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000114
Hom.:
0
Bravo
AF:
0.000280
ESP6500AA
AF:
0.000509
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000149
AC:
18
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 26, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1697C>T (p.P566L) alteration is located in exon 3 (coding exon 3) of the STOX2 gene. This alteration results from a C to T substitution at nucleotide position 1697, causing the proline (P) at amino acid position 566 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
0.067
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
16
DANN
Benign
0.79
DEOGEN2
Benign
0.0074
T
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.55
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.0090
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.69
N
PhyloP100
2.3
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.097
Sift
Benign
0.10
T
Sift4G
Benign
0.24
T
Polyphen
0.0
B
Vest4
0.078
MVP
0.043
MPC
0.26
ClinPred
0.015
T
GERP RS
3.7
PromoterAI
-0.046
Neutral
Varity_R
0.056
gMVP
0.13
Mutation Taster
=99/1
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

Publications

Other links and lift over

dbSNP: rs199563171; hg19: chr4-184931688; API