Genetic Variant SHOX2:p.Leu129Leu (chr3-158105089-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_003030.4(SHOX2):c.387G>A(p.Leu129Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,449,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 25)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

SHOX2
NM_003030.4 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.488

Publications

1 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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>A		intron	N/A	NP_001157150.1	O60902-2
SHOX2	NM_003030.4		c.387G>A	p.Leu129Leu	synonymous	Exon 2 of 6	NP_003021.3	O60902-3
SHOX2	NM_006884.3		c.346+590G>A		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>A	p.Leu129Leu	synonymous	Exon 2 of 6	ENSP00000374240.4	O60902-3
SHOX2	ENST00000483851.7	TSL:2 MANE Select	c.346+590G>A		intron	N/A	ENSP00000419362.1	O60902-2
SHOX2	ENST00000554685.2	TSL:5	c.75G>A	p.Leu25Leu	synonymous	Exon 2 of 5	ENSP00000479329.1	A0A087WVB7

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

140320

Hom.:

Cov.:

show subpopulations

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:

0.000304

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000859

AC:

AN:

151336

AF XY:

0.0000868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000210

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000225

AC:

294

AN:

1309266

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

147

AN XY:

645044

show subpopulations

African (AFR)

AF:

0.0000343

AC:

AN:

29180

American (AMR)

AF:

0.000121

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:

0.0000128

AC:

AN:

78284

European-Finnish (FIN)

AF:

0.0000711

AC:

AN:

42198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4236

European-Non Finnish (NFE)

AF:

0.000273

AC:

279

AN:

1020404

Other (OTH)

AF:

0.000116

AC:

AN:

51904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000143

AC:

AN:

140320

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

67164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38140

American (AMR)

AF:

0.00

AC:

AN:

12898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3358

East Asian (EAS)

AF:

0.00

AC:

AN:

4472

South Asian (SAS)

AF:

0.00

AC:

AN:

4136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000304

AC:

AN:

65776

Other (OTH)

AF:

0.00

AC:

AN:

1966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000383

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.3

(source)

DANN

Benign

0.79

PhyloP100

0.49

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over