3-158098135-G-C

Variant names:

• chr3-158098135-G-C
• rs552279655
• NM_001163678.2:c.852C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001163678.2(SHOX2):​c.852C>G​(p.Ala284Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,613,368 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (10 hom.)
• Consequence: SHOX2 NM_001163678.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.640
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-158098135-G-C is Benign according to our data. Variant chr3-158098135-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2654254.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.64 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2	c.852C>G	p.Ala284Ala	synonymous_variant	Exon 5 of 5	ENST00000483851.7	NP_001157150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX2	ENST00000483851.7	c.852C>G	p.Ala284Ala	synonymous_variant	Exon 5 of 5	2	NM_001163678.2	ENSP00000419362.1
SHOX2	ENST00000389589.8	c.960C>G	p.Ala320Ala	synonymous_variant	Exon 6 of 6	1		ENSP00000374240.4
SHOX2	ENST00000441443.6	c.888C>G	p.Ala296Ala	synonymous_variant	Exon 5 of 5	5		ENSP00000397099.3
SHOX2	ENST00000490689.3	n.2003C>G		non_coding_transcript_exon_variant	Exon 5 of 5	5

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152252 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000992 AC: 247 AN: 248968 AF XY: 0.00111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00224

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000647 AC: 945 AN: 1460998 Hom.: 10 Cov.: 31 AF XY: 0.000787 AC XY: 572 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00895 AC: 355 AN: 39684

South Asian (SAS) AF: 0.00623 AC: 537 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111574

Other (OTH) AF: 0.000679 AC: 41 AN: 60360

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152370 Hom.: 1 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5188

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.00462 AC: 16 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHOX2: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.9
DANN	Benign	0.81
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs552279655; hg19: chr3-157815924;