ENST00000389589.8:c.407T>G

Variant names:

• chr3-158105069-A-C
• rs1713794657
• ENST00000389589.8:c.407T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000389589.8(SHOX2):​c.407T>G​(p.Phe136Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHOX2 ENST00000389589.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0960
• Publications: 0 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.08340648).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000146 AC: 18 AN: 123530 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000543

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.000157

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000328

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00262 AC: 2645 AN: 1008956 Hom.: 0 Cov.: 21 AF XY: 0.00247 AC XY: 1243 AN XY: 503586

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00497 AC: 114 AN: 22926

American (AMR) AF: 0.00211 AC: 64 AN: 30304

Ashkenazi Jewish (ASJ) AF: 0.00596 AC: 106 AN: 17796

East Asian (EAS) AF: 0.0113 AC: 205 AN: 18070

South Asian (SAS) AF: 0.000247 AC: 18 AN: 72850

European-Finnish (FIN) AF: 0.0101 AC: 342 AN: 33948

Middle Eastern (MID) AF: 0.00628 AC: 19 AN: 3026

European-Non Finnish (NFE) AF: 0.00204 AC: 1570 AN: 770356

Other (OTH) AF: 0.00522 AC: 207 AN: 39680

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000146 AC: 18 AN: 123600 Hom.: 0 Cov.: 23 AF XY: 0.000120 AC XY: 7 AN XY: 58124

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000153 AC: 5 AN: 32604

American (AMR) AF: 0.000185 AC: 2 AN: 10798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3210

East Asian (EAS) AF: 0.000545 AC: 2 AN: 3670

South Asian (SAS) AF: 0.00184 AC: 6 AN: 3266

European-Finnish (FIN) AF: 0.000157 AC: 1 AN: 6372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.0000328 AC: 2 AN: 60922

Other (OTH) AF: 0.00 AC: 0 AN: 1694

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407T>G (p.F136C) alteration is located in exon 2 (coding exon 2) of the SHOX2 gene. This alteration results from a T to G substitution at nucleotide position 407, causing the phenylalanine (F) at amino acid position 136 to be replaced by a cysteine (C). 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
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.6
DANN	Benign	0.48
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.096
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.18	T
Polyphen		0.12	B
Vest4		0.20
MutPred		0.30		Gain of glycosylation at S141 (P = 0.0287);
MVP		0.22
MPC		0.81
ClinPred		0.12	T
GERP RS		-0.094
gMVP		0.38
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1713794657; hg19: chr3-157822858;