Variant 3-158105714-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001163678.2(SHOX2):c.311G>C(p.Arg104Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000788 in 1,522,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000080 ( 0 hom. )

Consequence

SHOX2
NM_001163678.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.02

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3522329).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHOX2	NM_001163678.2 linkuse as main transcript	c.311G>C	p.Arg104Thr	missense_variant	1/5	ENST00000483851.7
SHOX2	NM_003030.4 linkuse as main transcript	c.311G>C	p.Arg104Thr	missense_variant	1/6
SHOX2	NM_006884.3 linkuse as main transcript	c.311G>C	p.Arg104Thr	missense_variant	1/5
SHOX2	XM_006713727.4 linkuse as main transcript	c.311G>C	p.Arg104Thr	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX2	ENST00000483851.7 linkuse as main transcript	c.311G>C	p.Arg104Thr	missense_variant	1/5	2	NM_001163678.2	P4	O60902-2
SHOX2	ENST00000389589.8 linkuse as main transcript	c.311G>C	p.Arg104Thr	missense_variant	1/6	1			O60902-3
SHOX2	ENST00000441443.6 linkuse as main transcript	c.311G>C	p.Arg104Thr	missense_variant	1/5	5		A1	O60902-1
SHOX2	ENST00000554685.2 linkuse as main transcript	c.6G>C	p.Glu2Asp	missense_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000803

AC:

AN:

1369900

Hom.:

Cov.:

AF XY:

0.00000739

AC XY:

AN XY:

676252

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:

0.0000103

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000977

AC:

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 submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.311G>C (p.R104T) alteration is located in exon 1 (coding exon 1) of the SHOX2 gene. This alteration results from a G to C substitution at nucleotide position 311, causing the arginine (R) at amino acid position 104 to be replaced by a threonine (T). 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

0.23

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.18

T;.;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

T;T;T

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.1

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.2

.;N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.0080

.;D;D

Sift4G

Benign

0.34

T;T;T

Polyphen

0.30

B;P;B

Vest4

0.64

MutPred

0.27

Gain of glycosylation at S105 (P = 0.0155);Gain of glycosylation at S105 (P = 0.0155);Gain of glycosylation at S105 (P = 0.0155);

MVP

0.85

MPC

1.6

ClinPred

0.94

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.52

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over