Genetic Variant ENST00000389589.8:c.407T>C (chr3-158105069-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000389589.8(SHOX2):c.407T>C(p.Phe136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict 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. F136C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SHOX2
ENST00000389589.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0960

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061237723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2 link	c.346+610T>C		intron_variant	Intron 1 of 4	ENST00000483851.7	NP_001157150.1	O60902-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX2	ENST00000483851.7 link	c.346+610T>C		intron_variant	Intron 1 of 4	2	NM_001163678.2	ENSP00000419362.1		O60902-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1010768

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

504458

African (AFR)

AF:

0.00

AC:

AN:

22968

American (AMR)

AF:

0.00

AC:

AN:

30342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17846

East Asian (EAS)

AF:

0.00

AC:

AN:

18186

South Asian (SAS)

AF:

0.00

AC:

AN:

72874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3036

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

771538

Other (OTH)

AF:

0.00

AC:

AN:

39810

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.9

(source)

DANN

Benign

0.71

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.30

M_CAP

Benign

0.0034

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.99

PhyloP100

0.096

PrimateAI

Benign

0.42

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.12

MutPred

0.26

Gain of glycosylation at S141 (P = 0.0287);

MVP

0.22

MPC

0.98

ClinPred

0.035

GERP RS

-0.094

gMVP

0.44

Mutation Taster

=100/0

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over