3-158105069-A-C

Variant summary

Our verdict is Likely benign. Variant got -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. 11/15 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX2	NM_001163678.2	c.346+610T>G		intron_variant		ENST00000483851.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX2	ENST00000483851.7	c.346+610T>G		intron_variant		2	NM_001163678.2	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 18 AN: 123530 Hom.: 0 Cov.: 23 FAILED QC

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

Gnomad4 AFR exome AF: 0.00497

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00596

Gnomad4 EAS exome AF: 0.0113

Gnomad4 SAS exome AF: 0.000247

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00522

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

Gnomad4 AFR AF: 0.000153

Gnomad4 AMR AF: 0.000185

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000545

Gnomad4 SAS AF: 0.00184

Gnomad4 FIN AF: 0.000157

Gnomad4 NFE AF: 0.0000328

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

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
MutationTaster	Benign	1.0	D;D;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1713794657; hg19: chr3-157822858;