X-124022649-C-A

Position:

• chrX-124022649-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_001042750.2(STAG2):​c.22C>A​(p.Pro8Thr) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: STAG2 NM_001042750.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.55

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAG2. . Gene score misZ 4.938 (greater than the threshold 3.09). GenCC has associacion of gene with Mullegama-Klein-Martinez syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19669196).
• BP6: Variant X-124022649-C-A is Benign according to our data. Variant chrX-124022649-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1900255.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAG2	NM_001042750.2	c.22C>A	p.Pro8Thr	missense_variant	3/35	ENST00000371145.8	NP_001036215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAG2	ENST00000371145.8	c.22C>A	p.Pro8Thr	missense_variant	3/35	1	NM_001042750.2	ENSP00000360187.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with STAG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8 of the STAG2 protein (p.Pro8Thr). -

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

Likely benign, criteria provided, single submitter

clinical testing

3billion

Sep 20, 2024

The hemizygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the hemizygous variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.69
DEOGEN2	Benign	0.019	.;T;.;.;T;.;T;.;T;.;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;.;D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	.;.;N;.;N;.;N;N;N;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.8	D;N;N;D;N;N;N;N;N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;.;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.079	.;.;B;.;B;.;B;B;B;.;.;.
Vest4		0.22, 0.23, 0.23, 0.22
MutPred		0.35		Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);Gain of glycosylation at P8 (P = 0.017);
MVP		0.32
MPC		1.3
ClinPred		0.75	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.61

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-123156499;