X-124366141-T-G

Variant names:

• chrX-124366141-T-G
• rs2049995
• NM_002351.5:c.201+317T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_002351.5(SH2D1A):​c.201+317T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.81 (25515 hom., 25683 hem., cov: 21)
  • Failed GnomAD Quality Control
• Consequence: SH2D1A NM_002351.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.985
• Publications: 5 publications found

Genes affected

SH2D1A (HGNC:10820): (SH2 domain containing 1A) This gene encodes a protein that plays a major role in the bidirectional stimulation of T and B cells. This protein contains an SH2 domain and a short tail. It associates with the signaling lymphocyte-activation molecule, thereby acting as an inhibitor of this transmembrane protein by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to its docking site. This protein can also bind to other related surface molecules that are expressed on activated T, B and NK cells, thereby modifying signal transduction pathways in these cells. Mutations in this gene cause lymphoproliferative syndrome X-linked type 1 or Duncan disease, a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus, with symptoms including severe mononucleosis and malignant lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-124366141-T-G is Benign according to our data. Variant chrX-124366141-T-G is described in ClinVar as Benign. ClinVar VariationId is 1278483.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002351.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	NM_002351.5	MANE Select	c.201+317T>G		intron	N/A	NP_002342.1
	SH2D1A	NM_001114937.3		c.201+317T>G		intron	N/A	NP_001108409.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	ENST00000371139.9	TSL:1 MANE Select	c.201+317T>G		intron	N/A	ENSP00000360181.5
	SH2D1A	ENST00000360027.5	TSL:1	c.201+317T>G		intron	N/A	ENSP00000353126.4
	SH2D1A	ENST00000494073.5	TSL:1	c.138-4090T>G		intron	N/A	ENSP00000513589.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 88394 AN: 109473 Hom.: 25515 Cov.: 21

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.939

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.873

Gnomad MID AF: 0.735

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.799

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.807 AC: 88403 AN: 109526 Hom.: 25515 Cov.: 21 AF XY: 0.808 AC XY: 25683 AN XY: 31788

African (AFR) AF: 0.712 AC: 21413 AN: 30090

American (AMR) AF: 0.889 AC: 9074 AN: 10211

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 1891 AN: 2623

East Asian (EAS) AF: 0.938 AC: 3294 AN: 3510

South Asian (SAS) AF: 0.763 AC: 1922 AN: 2520

European-Finnish (FIN) AF: 0.873 AC: 4853 AN: 5557

Middle Eastern (MID) AF: 0.736 AC: 156 AN: 212

European-Non Finnish (NFE) AF: 0.837 AC: 44052 AN: 52653

Other (OTH) AF: 0.800 AC: 1185 AN: 1481

Alfa AF: 0.788 Hom.: 11172

Bravo AF: 0.808

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.3
DANN	Benign	0.64
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

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: rs2049995; hg19: chrX-123499991;