rs142921456

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001163678.2(SHOX2):​c.760C>T​(p.Pro254Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P254T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

SHOX2
NM_001163678.2 missense

Scores

8
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.34

Publications

3 publications found
Variant links:
Genes affected
SHOX2 (HGNC:10854): (SHOX homeobox 2) This gene is a member of the homeobox family of genes that encode proteins containing a 60-amino acid residue motif that represents a DNA binding domain. Homeobox genes have been characterized extensively as transcriptional regulators involved in pattern formation in both invertebrate and vertebrate species. Several human genetic disorders are caused by aberrations in human homeobox genes. This locus represents a pseudoautosomal homeobox gene that is thought to be responsible for idiopathic short stature, and it is implicated in the short stature phenotype of Turner syndrome patients. This gene is considered to be a candidate gene for Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]
SHOX2 Gene-Disease associations (from GenCC):
  • schizophrenia
    Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13113666).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHOX2NM_001163678.2 linkc.760C>T p.Pro254Ser missense_variant Exon 5 of 5 ENST00000483851.7 NP_001157150.1 O60902-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHOX2ENST00000483851.7 linkc.760C>T p.Pro254Ser missense_variant Exon 5 of 5 2 NM_001163678.2 ENSP00000419362.1 O60902-2
SHOX2ENST00000389589.8 linkc.868C>T p.Pro290Ser missense_variant Exon 6 of 6 1 ENSP00000374240.4 O60902-3
SHOX2ENST00000441443.6 linkc.796C>T p.Pro266Ser missense_variant Exon 5 of 5 5 ENSP00000397099.3 O60902-1
SHOX2ENST00000490689.3 linkn.1911C>T non_coding_transcript_exon_variant Exon 5 of 5 5

Frequencies

GnomAD3 genomes
AF:
0.0000985
AC:
15
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000926
AC:
23
AN:
248490
AF XY:
0.0000520
show subpopulations
Gnomad AFR exome
AF:
0.0000620
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.0000996
Gnomad EAS exome
AF:
0.000109
Gnomad FIN exome
AF:
0.0000927
Gnomad NFE exome
AF:
0.0000899
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000486
AC:
71
AN:
1461604
Hom.:
0
Cov.:
31
AF XY:
0.0000426
AC XY:
31
AN XY:
727120
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.0000895
AC:
4
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26110
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39694
South Asian (SAS)
AF:
0.000128
AC:
11
AN:
86214
European-Finnish (FIN)
AF:
0.000150
AC:
8
AN:
53368
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000360
AC:
40
AN:
1111894
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
5
10
14
19
24
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.0000984
AC:
15
AN:
152366
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74506
show subpopulations
African (AFR)
AF:
0.000144
AC:
6
AN:
41586
American (AMR)
AF:
0.0000653
AC:
1
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4834
European-Finnish (FIN)
AF:
0.000282
AC:
3
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.515
Heterozygous variant carriers
0
1
2
2
3
4
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:
0.0000364
Hom.:
0
Bravo
AF:
0.0000793
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;.;.;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Uncertain
0.79
D
MutationAssessor
Benign
0.28
N;.;.;.
PhyloP100
4.3
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-2.1
.;.;.;N
REVEL
Uncertain
0.35
Sift
Benign
0.10
.;.;.;T
Sift4G
Benign
0.17
T;T;T;T
Polyphen
1.0
D;.;P;B
Vest4
0.085
MVP
0.93
MPC
0.91
ClinPred
0.059
T
GERP RS
5.1
Varity_R
0.23
gMVP
0.53
Mutation Taster
=62/38
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: rs142921456; hg19: chr3-157816016; COSMIC: COSV67463402; COSMIC: COSV67463402; API