1-156809672-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003975.4(SH2D2A):​c.703G>A​(p.Gly235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,610,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SH2D2A
NM_003975.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.18
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.049339294).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SH2D2ANM_003975.4 linkuse as main transcriptc.703G>A p.Gly235Arg missense_variant 6/9 ENST00000368199.8 NP_003966.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SH2D2AENST00000368199.8 linkuse as main transcriptc.703G>A p.Gly235Arg missense_variant 6/91 NM_003975.4 ENSP00000357182 P2Q9NP31-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152258
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
247910
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
134178
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000299
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000890
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1458660
Hom.:
0
Cov.:
33
AF XY:
0.0000138
AC XY:
10
AN XY:
725688
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000230
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2023The c.733G>A (p.G245R) alteration is located in exon 6 (coding exon 6) of the SH2D2A gene. This alteration results from a G to A substitution at nucleotide position 733, causing the glycine (G) at amino acid position 245 to be replaced by an arginine (R). 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
0.079
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
0.028
DANN
Benign
0.70
DEOGEN2
Benign
0.33
.;T;.
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.022
N
LIST_S2
Benign
0.39
T;T;T
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.049
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.5
.;L;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.1
N;N;N
REVEL
Benign
0.083
Sift
Benign
0.15
T;T;T
Sift4G
Benign
0.27
T;T;T
Polyphen
0.0, 0.0040
.;B;B
Vest4
0.095
MutPred
0.24
.;Gain of helix (P = 0.027);.;
MVP
0.27
MPC
0.31
ClinPred
0.042
T
GERP RS
-2.3
Varity_R
0.070
gMVP
0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376035537; hg19: chr1-156779464; COSMIC: COSV100949204; COSMIC: COSV100949204; API