X-124022668-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001042750.2(STAG2):c.41T>A(p.Leu14Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 5.61

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STAG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.25738215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAG2	NM_001042750.2	c.41T>A	p.Leu14Gln	missense_variant	3/35	ENST00000371145.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAG2	ENST00000371145.8	c.41T>A	p.Leu14Gln	missense_variant	3/35	1	NM_001042750.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2023

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 14 of the STAG2 protein (p.Leu14Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STAG2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Benign	0.93
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;.;D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D;N;N;D;N;N;N;N;N;N;N;N
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;.;T;T;T;T;T;T;T;T
Polyphen		0.55, 0.41	.;.;P;.;B;.;B;P;B;.;.;.
Vest4		0.30, 0.28, 0.32, 0.29
MutPred		0.35		Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);
MVP		0.31
MPC		1.6
ClinPred		0.70	D
GERP RS		5.0
Varity_R		0.45
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-123156518;