Genetic Variant STAG2:c.45-11T>C (chrX-124025829-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001042750.2(STAG2):c.45-11T>C variant causes a intron change. The variant allele was found at a frequency of 0.000195 in 1,132,291 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 57 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., 29 hem., cov: 21)

Exomes 𝑓: 0.00011 ( 0 hom. 28 hem. )

Consequence

STAG2
NM_001042750.2 intron

Scores

Splicing: ADA: 0.1476

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.81

Publications

0 publications found

Variant links:

Genes affected

STAG2 (HGNC:11355): (STAG2 cohesin complex component) The protein encoded by this gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Targeted inactivation of this gene results in chromatid cohesion defects and aneuploidy, suggesting that genetic disruption of cohesin is a cause of aneuploidy in human cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

STAG2 Gene-Disease associations (from GenCC):

Mullegama-Klein-Martinez syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Xq25 microduplication syndrome
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

STAG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant X-124025829-T-C is Benign according to our data. Variant chrX-124025829-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1664876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 29 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042750.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STAG2	NM_001042750.2	MANE Select	c.45-11T>C	intron	N/A	NP_001036215.1	Q8N3U4-2
STAG2	NM_001042749.2		c.45-11T>C	intron	N/A	NP_001036214.1	Q8N3U4-2
STAG2	NM_001375366.1		c.45-11T>C	intron	N/A	NP_001362295.1	Q8N3U4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STAG2	ENST00000371145.8	TSL:1 MANE Select	c.45-11T>C	intron	N/A	ENSP00000360187.4	Q8N3U4-2
STAG2	ENST00000218089.13	TSL:1	c.45-11T>C	intron	N/A	ENSP00000218089.9	Q8N3U4-2
STAG2	ENST00000371144.7	TSL:1	c.45-11T>C	intron	N/A	ENSP00000360186.3	Q8N3U4-1

Frequencies

GnomAD3 genomes

AF:

0.000950

AC:

105

AN:

110484

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000293

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000343

AC:

AN:

151404

AF XY:

0.000168

show subpopulations

Gnomad AFR exome

AF:

0.00392

Gnomad AMR exome

AF:

0.000357

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

116

AN:

1021758

Hom.:

Cov.:

AF XY:

0.0000911

AC XY:

AN XY:

307522

show subpopulations

African (AFR)

AF:

0.00388

AC:

AN:

23943

American (AMR)

AF:

0.000277

AC:

AN:

28909

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17749

East Asian (EAS)

AF:

0.00

AC:

AN:

28312

South Asian (SAS)

AF:

0.0000226

AC:

AN:

44316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39394

Middle Eastern (MID)

AF:

0.000771

AC:

AN:

3892

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

792206

Other (OTH)

AF:

0.000256

AC:

AN:

43037

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000950

AC:

105

AN:

110533

Hom.:

Cov.:

AF XY:

0.000885

AC XY:

AN XY:

32785

show subpopulations

African (AFR)

AF:

0.00334

AC:

102

AN:

30567

American (AMR)

AF:

0.000293

AC:

AN:

10234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.00

AC:

AN:

2689

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5637

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52804

Other (OTH)

AF:

0.00

AC:

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000608

Hom.:

Bravo

AF:

0.00108

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mullegama-Klein-Martinez syndrome;C5393308:Holoprosencephaly 13, X-linked (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.15

dbscSNV1_RF

Benign

0.33

SpliceAI score (max)

0.060

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over