X-124346695-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002351.5(SH2D1A):c.53A>G(p.Lys18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,210,301 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 8 hem. )

Consequence

SH2D1A
NM_002351.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

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]

SH2D1A links:

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, G2P, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Xq25 microduplication syndrome
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

STAG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16648412).

BP6

Variant X-124346695-A-G is Benign according to our data. Variant chrX-124346695-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450974.

BS2

High Hemizygotes in GnomAdExome4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	NM_002351.5	MANE Select	c.53A>G	p.Lys18Arg	missense	Exon 1 of 4	NP_002342.1	O60880-1
	SH2D1A	NM_001114937.3		c.53A>G	p.Lys18Arg	missense	Exon 1 of 4	NP_001108409.1	O60880-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2D1A	ENST00000371139.9	TSL:1 MANE Select	c.53A>G	p.Lys18Arg	missense	Exon 1 of 4	ENSP00000360181.5	O60880-1
SH2D1A	ENST00000360027.5	TSL:1	c.53A>G	p.Lys18Arg	missense	Exon 1 of 4	ENSP00000353126.4	O60880-4
SH2D1A	ENST00000494073.5	TSL:1	c.53A>G	p.Lys18Arg	missense	Exon 1 of 3	ENSP00000513589.1	O60880-6

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183424

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000209

AC:

AN:

1097895

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363257

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000273

AC:

AN:

841845

Other (OTH)

AF:

0.00

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112406

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30951

American (AMR)

AF:

0.00

AC:

AN:

10684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53228

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

X-linked lymphoproliferative disease due to SH2D1A deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.73

M_CAP

Benign

0.065

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.65

MutationAssessor

Benign

-0.050

PhyloP100

1.3

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.63

REVEL

Benign

0.20

Sift

Benign

0.41

Sift4G

Benign

0.53

Polyphen

0.0070

Vest4

0.16

MVP

0.88

MPC

0.99

ClinPred

0.17

GERP RS

1.9

PromoterAI

-0.078

Neutral

(source)

Varity_R

0.12

gMVP

0.77

Mutation Taster

=87/13

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over