3-158100311-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001163678.2(SHOX2):​c.556G>A​(p.Val186Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,444,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SHOX2
NM_001163678.2 missense, splice_region

Scores

11
5
3
Splicing: ADA: 0.9997
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.749
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SHOX2NM_001163678.2 linkuse as main transcriptc.556G>A p.Val186Ile missense_variant, splice_region_variant 3/5 ENST00000483851.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SHOX2ENST00000483851.7 linkuse as main transcriptc.556G>A p.Val186Ile missense_variant, splice_region_variant 3/52 NM_001163678.2 P4O60902-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000485
AC:
7
AN:
1444414
Hom.:
0
Cov.:
29
AF XY:
0.00000418
AC XY:
3
AN XY:
718142
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000632
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 24, 2023The c.628G>A (p.V210I) alteration is located in exon 4 (coding exon 4) of the SHOX2 gene. This alteration results from a G to A substitution at nucleotide position 628, causing the valine (V) at amino acid position 210 to be replaced by an isoleucine (I). 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
0.99
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;.;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.75
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
0.92
L;.;.;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.0
.;.;.;N
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
.;.;.;D
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
1.0
D;.;D;D
Vest4
0.56
MutPred
0.79
Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);
MVP
0.98
MPC
1.4
ClinPred
0.96
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1380735730; hg19: chr3-157818100; API