NM_001163678.2:c.161C>T

Variant names:

• chr3-158105864-G-A
• NM_001163678.2:c.161C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001163678.2(SHOX2):​c.161C>T​(p.Pro54Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33588663).

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.161C>T	p.Pro54Leu	missense	Exon 1 of 5	NP_001157150.1	O60902-2
	SHOX2	NM_003030.4		c.161C>T	p.Pro54Leu	missense	Exon 1 of 6	NP_003021.3	O60902-3
	SHOX2	NM_006884.3		c.161C>T	p.Pro54Leu	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.161C>T	p.Pro54Leu	missense	Exon 1 of 5	ENSP00000419362.1	O60902-2
	SHOX2	ENST00000389589.8	TSL:1	c.161C>T	p.Pro54Leu	missense	Exon 1 of 6	ENSP00000374240.4	O60902-3
	SHOX2	ENST00000441443.6	TSL:5	c.161C>T	p.Pro54Leu	missense	Exon 1 of 5	ENSP00000397099.3	O60902-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1341352 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 661416

African (AFR) AF: 0.00 AC: 0 AN: 26580

American (AMR) AF: 0.00 AC: 0 AN: 24860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22758

East Asian (EAS) AF: 0.00 AC: 0 AN: 28714

South Asian (SAS) AF: 0.00 AC: 0 AN: 72370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1058146

Other (OTH) AF: 0.00 AC: 0 AN: 55338

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.0070
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.25	T
Polyphen		0.97	D
Vest4		0.52
MutPred		0.31		Gain of glycosylation at S52 (P = 0.0106)
MVP		0.84
MPC		0.71
ClinPred		0.59	D
GERP RS		3.9
PromoterAI		-0.0046	Neutral
Varity_R		0.27
gMVP		0.21
Mutation Taster		=77/23	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

hg19: chr3-157823653;