3-158105682-C-G

Variant names:

• chr3-158105682-C-G
• rs1053371191
• NM_001163678.2:c.343G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001163678.2(SHOX2):​c.343G>C​(p.Glu115Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000729 in 1,371,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E115K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.63
• 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]

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]

RSRC1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 70

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17202488).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163678.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX2	NM_001163678.2	MANE Select	c.343G>C	p.Glu115Gln	missense	Exon 1 of 5	NP_001157150.1	O60902-2
	SHOX2	NM_003030.4		c.343G>C	p.Glu115Gln	missense	Exon 1 of 6	NP_003021.3	O60902-3
	SHOX2	NM_006884.3		c.343G>C	p.Glu115Gln	missense	Exon 1 of 5	NP_006875.2	O60902-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX2	ENST00000483851.7	TSL:2 MANE Select	c.343G>C	p.Glu115Gln	missense	Exon 1 of 5	ENSP00000419362.1	O60902-2
	SHOX2	ENST00000389589.8	TSL:1	c.343G>C	p.Glu115Gln	missense	Exon 1 of 6	ENSP00000374240.4	O60902-3
	RSRC1	ENST00000948232.1		c.-270C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000618291.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 118724 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371552 Hom.: 0 Cov.: 33 AF XY: 0.00000148 AC XY: 1 AN XY: 677372

African (AFR) AF: 0.00 AC: 0 AN: 28524

American (AMR) AF: 0.00 AC: 0 AN: 33494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24184

East Asian (EAS) AF: 0.00 AC: 0 AN: 31298

South Asian (SAS) AF: 0.00 AC: 0 AN: 78012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069572

Other (OTH) AF: 0.00 AC: 0 AN: 56906

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.078
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.037
Sift	Benign	0.036	D
Sift4G	Benign	0.32	T
Polyphen		0.083	B
Vest4		0.13
MutPred		0.22		Gain of glycosylation at S110 (P = 0.0054)
MVP		0.65
MPC		0.94
ClinPred		0.90	D
GERP RS		3.4
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.39
Mutation Taster		=75/25	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: rs1053371191; hg19: chr3-157823471;