chr3-158098169-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001163678.2(SHOX2):c.818C>A(p.Pro273Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SHOX2
NM_001163678.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.62

Publications

0 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)

SHOX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2 link	c.818C>A	p.Pro273Gln	missense_variant	Exon 5 of 5	ENST00000483851.7	NP_001157150.1	O60902-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHOX2	ENST00000483851.7 link	c.818C>A	p.Pro273Gln	missense_variant	Exon 5 of 5	2	NM_001163678.2	ENSP00000419362.1	O60902-2
SHOX2	ENST00000389589.8 link	c.926C>A	p.Pro309Gln	missense_variant	Exon 6 of 6	1		ENSP00000374240.4	O60902-3
SHOX2	ENST00000441443.6 link	c.854C>A	p.Pro285Gln	missense_variant	Exon 5 of 5	5		ENSP00000397099.3	O60902-1
SHOX2	ENST00000490689.3 link	n.1969C>A		non_coding_transcript_exon_variant	Exon 5 of 5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248938

AF XY:

0.00

show subpopulations

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:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461116

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111666

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.926C>A (p.P309Q) alteration is located in exon 6 (coding exon 6) of the SHOX2 gene. This alteration results from a C to A substitution at nucleotide position 926, causing the proline (P) at amino acid position 309 to be replaced by a glutamine (Q). 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

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.81

L;.;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.1

.;.;.;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.010

.;.;.;D

Sift4G

Benign

0.10

T;T;T;D

Polyphen

1.0

D;.;D;D

Vest4

0.67

MutPred

0.41

Gain of catalytic residue at P285 (P = 0.007);.;.;.;

MVP

0.94

MPC

1.5

ClinPred

0.98

GERP RS

5.0

Varity_R

0.37

gMVP

0.72

Mutation Taster

=4/96

disease causing

(source)

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

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chr3-158098169-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over