Genetic Variant SH2D2A:p.Gly351Val (chr1-156807296-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003975.4(SH2D2A):c.1052G>T(p.Gly351Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,593,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SH2D2A
NM_003975.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.110

Publications

0 publications found

Variant links:

Genes affected

SH2D2A (HGNC:10821): (SH2 domain containing 2A) This gene encodes an adaptor protein thought to function in T-cell signal transduction. A related protein in mouse is responsible for the activation of lymphocyte-specific protein-tyrosine kinase and functions in downstream signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

SH2D2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12597525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D2A	NM_003975.4 link	c.1052G>T	p.Gly351Val	missense_variant	Exon 8 of 9	ENST00000368199.8	NP_003966.2	Q9NP31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH2D2A	ENST00000368199.8 link	c.1052G>T	p.Gly351Val	missense_variant	Exon 8 of 9	1	NM_003975.4	ENSP00000357182.3	Q9NP31-1
SH2D2A	ENST00000392306.2 link	c.1082G>T	p.Gly361Val	missense_variant	Exon 8 of 9	1		ENSP00000376123.2	Q9NP31-2
SH2D2A	ENST00000368198.8 link	c.998G>T	p.Gly333Val	missense_variant	Exon 8 of 9	1		ENSP00000357181.3	Q9NP31-4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152072

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000230

AC:

AN:

217668

AF XY:

0.0000253

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000408

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000160

AC:

AN:

1441642

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

716288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33264

American (AMR)

AF:

0.0000231

AC:

AN:

43330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25580

East Asian (EAS)

AF:

0.00

AC:

AN:

39432

South Asian (SAS)

AF:

0.00

AC:

AN:

84558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

1106156

Other (OTH)

AF:

0.0000501

AC:

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1082G>T (p.G361V) alteration is located in exon 8 (coding exon 8) of the SH2D2A gene. This alteration results from a G to T substitution at nucleotide position 1082, causing the glycine (G) at amino acid position 361 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

.;D;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

2.0

.;M;.

PhyloP100

0.11

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.91, 1.0

.;P;D

Vest4

0.15

MutPred

0.24

.;Gain of sheet (P = 0.039);.;

MVP

0.85

MPC

1.0

ClinPred

0.57

GERP RS

1.3

Varity_R

0.20

gMVP

0.19

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-156807296-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over