X-124022632-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001042750.2(STAG2):c.5T>C(p.Ile2Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: STAG2 NM_001042750.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STAG2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAG2	NM_001042750.2	c.5T>C	p.Ile2Thr	missense_variant	3/35	ENST00000371145.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAG2	ENST00000371145.8	c.5T>C	p.Ile2Thr	missense_variant	3/35	1	NM_001042750.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mullegama-Klein-Martinez syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 19, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;.;D;.;D;.;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.0	D;N;N;D;N;N;N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.0040	.;.;D;.;B;.;B;D;B;.;.;.
Vest4		0.62, 0.67, 0.68, 0.64, 0.67
MutPred		0.40		Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);Gain of glycosylation at I2 (P = 0.0019);
MVP		0.39
MPC		2.6
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2056968861; hg19: chrX-123156482;