X-124346690-C-T

Variant names:

• chrX-124346690-C-T
• rs72610640
• NM_002351.5:c.48C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002351.5(SH2D1A):​c.48C>T​(p.Gly16Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,210,010 control chromosomes in the GnomAD database, including 3 homozygotes. There are 1,222 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 51 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (3 hom. 1171 hem.)
• Consequence: SH2D1A NM_002351.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0130
• Publications: 2 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant X-124346690-C-T is Benign according to our data. Variant chrX-124346690-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.013 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 51 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	NM_002351.5	MANE Select	c.48C>T	p.Gly16Gly	synonymous	Exon 1 of 4	NP_002342.1
	SH2D1A	NM_001114937.3		c.48C>T	p.Gly16Gly	synonymous	Exon 1 of 4	NP_001108409.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	ENST00000371139.9	TSL:1 MANE Select	c.48C>T	p.Gly16Gly	synonymous	Exon 1 of 4	ENSP00000360181.5
	SH2D1A	ENST00000360027.5	TSL:1	c.48C>T	p.Gly16Gly	synonymous	Exon 1 of 4	ENSP00000353126.4
	SH2D1A	ENST00000494073.5	TSL:1	c.48C>T	p.Gly16Gly	synonymous	Exon 1 of 3	ENSP00000513589.1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 217 AN: 112345 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00355

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00198 AC: 363 AN: 183390 AF XY: 0.00201

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000628

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00327 AC: 3592 AN: 1097613 Hom.: 3 Cov.: 30 AF XY: 0.00323 AC XY: 1171 AN XY: 362979

African (AFR) AF: 0.000530 AC: 14 AN: 26393

American (AMR) AF: 0.00131 AC: 46 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 23 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54131

European-Finnish (FIN) AF: 0.000519 AC: 21 AN: 40490

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4136

European-Non Finnish (NFE) AF: 0.00399 AC: 3362 AN: 841607

Other (OTH) AF: 0.00265 AC: 122 AN: 46075

GnomAD4 genome AF: 0.00193 AC: 217 AN: 112397 Hom.: 0 Cov.: 23 AF XY: 0.00147 AC XY: 51 AN XY: 34591

African (AFR) AF: 0.000355 AC: 11 AN: 30995

American (AMR) AF: 0.00112 AC: 12 AN: 10686

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2713

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00355 AC: 189 AN: 53215

Other (OTH) AF: 0.00197 AC: 3 AN: 1525

Alfa AF: 0.000801 Hom.: 7

Bravo AF: 0.00203

EpiCase AF: 0.00273

EpiControl AF: 0.00415

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	X-linked lymphoproliferative disease due to SH2D1A deficiency (2)
-	-	1	Mullegama-Klein-Martinez syndrome;C5393308:Holoprosencephaly 13, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.9
DANN	Benign	0.85
PhyloP100		-0.013
PromoterAI		0.10	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs72610640; hg19: chrX-123480540; COSMIC: COSV63579295;