rs372118088

Variant names:

• chrX-124025922-T-C
• rs372118088
• NM_001042750.2:c.123+4T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001042750.2(STAG2):​c.123+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,141,301 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 9 hem., cov: 21)
  • Exomes 𝑓: 0.00024 (0 hom. 72 hem.)
• Consequence: STAG2 NM_001042750.2 splice_region, intron
• Scores: Splicing: ADA: 0.003827
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.938
• Publications: 0 publications found

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, Labcorp Genetics (formerly Invitae), Illumina
• Xq25 microduplication syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-124025922-T-C is Benign according to our data. Variant chrX-124025922-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1164890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAG2	NM_001042750.2	MANE Select	c.123+4T>C		splice_region intron	N/A	NP_001036215.1	Q8N3U4-2
	STAG2	NM_001042749.2		c.123+4T>C		splice_region intron	N/A	NP_001036214.1	Q8N3U4-2
	STAG2	NM_001375366.1		c.123+4T>C		splice_region intron	N/A	NP_001362295.1	Q8N3U4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAG2	ENST00000371145.8	TSL:1 MANE Select	c.123+4T>C		splice_region intron	N/A	ENSP00000360187.4	Q8N3U4-2
	STAG2	ENST00000218089.13	TSL:1	c.123+4T>C		splice_region intron	N/A	ENSP00000218089.9	Q8N3U4-2
	STAG2	ENST00000371144.7	TSL:1	c.123+4T>C		splice_region intron	N/A	ENSP00000360186.3	Q8N3U4-1

Frequencies

GnomAD3 genomes AF: 0.000182 AC: 20 AN: 110054 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

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: 0.000209

Gnomad OTH AF: 0.00135

GnomAD2 exomes AF: 0.000114 AC: 19 AN: 166706 AF XY: 0.000128

Gnomad AFR exome AF: 0.0000824

Gnomad AMR exome AF: 0.000170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.000253

GnomAD4 exome AF: 0.000240 AC: 247 AN: 1031247 Hom.: 0 Cov.: 20 AF XY: 0.000235 AC XY: 72 AN XY: 306409

African (AFR) AF: 0.00 AC: 0 AN: 24756

American (AMR) AF: 0.000243 AC: 8 AN: 32984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18590

East Asian (EAS) AF: 0.00 AC: 0 AN: 29033

South Asian (SAS) AF: 0.00 AC: 0 AN: 48993

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39993

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3962

European-Non Finnish (NFE) AF: 0.000290 AC: 229 AN: 789277

Other (OTH) AF: 0.000229 AC: 10 AN: 43659

GnomAD4 genome AF: 0.000182 AC: 20 AN: 110054 Hom.: 0 Cov.: 21 AF XY: 0.000278 AC XY: 9 AN XY: 32326

African (AFR) AF: 0.0000329 AC: 1 AN: 30417

American (AMR) AF: 0.000590 AC: 6 AN: 10168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2635

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000209 AC: 11 AN: 52733

Other (OTH) AF: 0.00135 AC: 2 AN: 1483

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000238

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		0.94
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0038
dbscSNV1_RF	Benign	0.050
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

Other links and lift over

dbSNP: rs372118088; hg19: chrX-123159772;