X-124022662-A-G

Position:

• chrX-124022662-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001042750.2(STAG2):​c.35A>G​(p.Asn12Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000771 in 1,037,221 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 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)
  • Exomes 𝑓: 0.0000077 (0 hom. 5 hem.)
• Consequence: STAG2 NM_001042750.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

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 Likely_benign. Variant got -5 ACMG points.

• 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=0.095148355).
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAG2	NM_001042750.2	c.35A>G	p.Asn12Ser	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.35A>G	p.Asn12Ser	missense_variant	3/35	1	NM_001042750.2	ENSP00000360187.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000771 AC: 8 AN: 1037221 Hom.: 0 Cov.: 21 AF XY: 0.0000157 AC XY: 5 AN XY: 317953

Gnomad4 AFR exome AF: 0.000166

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000912

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 12 of the STAG2 protein (p.Asn12Ser). 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. ClinVar contains an entry for this variant (Variation ID: 1915600). 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	0.060
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.020	.;T;.;.;T;.;T;.;T;.;.;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D;D;.;D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.095	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	.;.;N;.;N;.;N;N;N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D;N;N;D;N;N;N;N;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.11	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, 0.0010	.;.;B;.;B;.;B;B;B;.;.;.
Vest4		0.058, 0.037, 0.041, 0.062, 0.040
MutPred		0.17		Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);Gain of glycosylation at N12 (P = 0.0351);
MVP		0.50
MPC		0.93
ClinPred		0.19	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.35

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: rs899950130; hg19: chrX-123156512;