rs1556571924

Variant names:

• chrX-124090634-C-A
• rs1556571924
• NM_001042750.2:c.3337C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-124090634-C-A
• chrX-124090634-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001042750.2(STAG2):​c.3337C>A​(p.Pro1113Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,400 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1113S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: STAG2 NM_001042750.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38
• 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
• Xq25 microduplication syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41102242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAG2	NM_001042750.2	c.3337C>A	p.Pro1113Thr	missense_variant	Exon 31 of 35	ENST00000371145.8	NP_001036215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAG2	ENST00000371145.8	c.3337C>A	p.Pro1113Thr	missense_variant	Exon 31 of 35	1	NM_001042750.2	ENSP00000360187.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097400 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362762

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54115

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841368

Other (OTH) AF: 0.0000217 AC: 1 AN: 46069

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;T;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	2.0	M;M;M;M;M
PhyloP100		7.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.032	D;T;T;D;T
Sift4G	Benign	0.37	T;T;T;T;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.49
MutPred		0.20		Gain of MoRF binding (P = 0.0662);Gain of MoRF binding (P = 0.0662);Gain of MoRF binding (P = 0.0662);Gain of MoRF binding (P = 0.0662);Gain of MoRF binding (P = 0.0662);
MVP		0.37
MPC		2.5
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.62
gMVP		0.74
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs1556571924; hg19: chrX-123224484;