3-158105856-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001163678.2(SHOX2):c.169C>G(p.Arg57Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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]

RSRC1 (HGNC:24152): (arginine and serine rich coiled-coil 1) This gene encodes a member of the serine and arginine rich-related protein family. The encoded protein is involved in both constitutive and alternative mRNA splicing. This gene may be associated with schizophrenia. A pseudogene of this gene is located on chromosome 9. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26643568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX2	NM_001163678.2	c.169C>G	p.Arg57Gly	missense_variant	1/5	ENST00000483851.7
SHOX2	NM_003030.4	c.169C>G	p.Arg57Gly	missense_variant	1/6
SHOX2	NM_006884.3	c.169C>G	p.Arg57Gly	missense_variant	1/5
SHOX2	XM_006713727.4	c.169C>G	p.Arg57Gly	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX2	ENST00000483851.7	c.169C>G	p.Arg57Gly	missense_variant	1/5	2	NM_001163678.2	P4
SHOX2	ENST00000389589.8	c.169C>G	p.Arg57Gly	missense_variant	1/6	1
SHOX2	ENST00000441443.6	c.169C>G	p.Arg57Gly	missense_variant	1/5	5		A1
RSRC1	ENST00000480820.5	c.-157G>C		5_prime_UTR_variant	1/10	5		P4

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151368 Hom.: 0 Cov.: 32

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151368 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73902

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: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

May 30, 2023

The c.169C>G (p.R57G) alteration is located in exon 1 (coding exon 1) of the SHOX2 gene. This alteration results from a C to G substitution at nucleotide position 169, causing the arginine (R) at amino acid position 57 to be replaced by a glycine (G). 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	0.079
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.95	D
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	B;P;P
Vest4		0.40
MutPred		0.36		Loss of methylation at R57 (P = 0.0068);Loss of methylation at R57 (P = 0.0068);Loss of methylation at R57 (P = 0.0068);
MVP		0.79
MPC		1.7
ClinPred		0.57	D
GERP RS		2.8
Varity_R		0.36
gMVP		0.55

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

Other links and lift over

dbSNP: rs780921313; hg19: chr3-157823645;