3-158105989-A-C

Variant names:

Variant summary

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

The NM_001163678.2(SHOX2):c.36T>G(p.Phe12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SHOX2
NM_001163678.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82

Publications

0 publications found

Variant links:

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 links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RSRC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2 link	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5	ENST00000483851.7	NP_001157150.1	O60902-2
SHOX2	NM_003030.4 link	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 6		NP_003021.3	O60902-3
SHOX2	NM_006884.3 link	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5		NP_006875.2	O60902-1
SHOX2	XM_006713727.4 link	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 6		XP_006713790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHOX2	ENST00000483851.7 link	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5	2	NM_001163678.2	ENSP00000419362.1	O60902-2
SHOX2	ENST00000389589.8 link	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 6	1		ENSP00000374240.4	O60902-3
SHOX2	ENST00000441443.6 link	c.36T>G	p.Phe12Leu	missense_variant	Exon 1 of 5	5		ENSP00000397099.3	O60902-1
RSRC1	ENST00000480820.5 link	c.-24A>C		5_prime_UTR_variant	Exon 1 of 10	5		ENSP00000420150.1	Q96IZ7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

245238

AF XY:

0.00000748

show subpopulations

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:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111752

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.36T>G (p.F12L) alteration is located in exon 1 (coding exon 1) of the SHOX2 gene. This alteration results from a T to G substitution at nucleotide position 36, causing the phenylalanine (F) at amino acid position 12 to be replaced by a leucine (L). 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.5

L;L;L

PhyloP100

1.8

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.5

.;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.034

.;D;D

Sift4G

Uncertain

0.053

T;D;T

Polyphen

0.53

P;D;B

Vest4

0.58

MutPred

0.36

Gain of glycosylation at S11 (P = 0.012);Gain of glycosylation at S11 (P = 0.012);Gain of glycosylation at S11 (P = 0.012);

MVP

0.94

MPC

1.6

ClinPred

0.94

GERP RS

1.4

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.27

gMVP

0.58

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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3-158105989-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over