Genetic Variant SHOX2:p.Leu129Leu (chr3-158105089-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_003030.4(SHOX2):c.387G>C(p.Leu129Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,309,272 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. Synonymous variant affecting the same amino acid position (i.e. L129L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

SHOX2
NM_003030.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.488

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 Gene-Disease associations (from GenCC):

atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SHOX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP7

Synonymous conserved (PhyloP=0.488 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003030.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHOX2	NM_001163678.2	MANE Select	c.346+590G>C		intron	N/A	NP_001157150.1	O60902-2
SHOX2	NM_003030.4		c.387G>C	p.Leu129Leu	synonymous	Exon 2 of 6	NP_003021.3	O60902-3
SHOX2	NM_006884.3		c.346+590G>C		intron	N/A	NP_006875.2	O60902-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHOX2	ENST00000389589.8	TSL:1	c.387G>C	p.Leu129Leu	synonymous	Exon 2 of 6	ENSP00000374240.4	O60902-3
SHOX2	ENST00000483851.7	TSL:2 MANE Select	c.346+590G>C		intron	N/A	ENSP00000419362.1	O60902-2
SHOX2	ENST00000554685.2	TSL:5	c.75G>C	p.Leu25Leu	synonymous	Exon 2 of 5	ENSP00000479329.1	A0A087WVB7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.64e-7

AC:

AN:

1309272

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

645048

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29180

American (AMR)

AF:

0.00

AC:

AN:

33022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21868

East Asian (EAS)

AF:

0.00

AC:

AN:

28170

South Asian (SAS)

AF:

0.00

AC:

AN:

78284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4236

European-Non Finnish (NFE)

AF:

9.80e-7

AC:

AN:

1020410

Other (OTH)

AF:

0.00

AC:

AN:

51904

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.8

(source)

DANN

Benign

0.61

PhyloP100

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over