1-156815121-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003975.4(SH2D2A):​c.224G>A​(p.Arg75Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,610,214 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

SH2D2A
NM_003975.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.139
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.080590636).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SH2D2ANM_003975.4 linkuse as main transcriptc.224G>A p.Arg75Gln missense_variant 3/9 ENST00000368199.8 NP_003966.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SH2D2AENST00000368199.8 linkuse as main transcriptc.224G>A p.Arg75Gln missense_variant 3/91 NM_003975.4 ENSP00000357182 P2Q9NP31-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152238
Hom.:
0
Cov.:
33
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:
0.000578
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000816
AC:
20
AN:
244986
Hom.:
0
AF XY:
0.000113
AC XY:
15
AN XY:
132494
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000102
Gnomad EAS exome
AF:
0.000612
Gnomad SAS exome
AF:
0.0000335
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000632
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000336
AC:
49
AN:
1457858
Hom.:
0
Cov.:
29
AF XY:
0.0000441
AC XY:
32
AN XY:
725076
show subpopulations
Gnomad4 AFR exome
AF:
0.0000601
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000385
Gnomad4 EAS exome
AF:
0.000203
Gnomad4 SAS exome
AF:
0.0000351
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000665
GnomAD4 genome
AF:
0.0000459
AC:
7
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.0000268
AC XY:
2
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000579
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000104
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000412
AC:
5

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 GeneticsMar 07, 2024The c.224G>A (p.R75Q) alteration is located in exon 3 (coding exon 3) of the SH2D2A gene. This alteration results from a G to A substitution at nucleotide position 224, causing the arginine (R) at amino acid position 75 to be replaced by a glutamine (Q). 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
0.097
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
19
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.36
.;T;.
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.75
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.081
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
.;L;L
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.11
Sift
Uncertain
0.024
D;D;D
Sift4G
Benign
0.089
T;T;T
Polyphen
1.0
.;D;D
Vest4
0.27
MVP
0.80
MPC
0.49
ClinPred
0.063
T
GERP RS
1.2
Varity_R
0.088
gMVP
0.33

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: rs199618683; hg19: chr1-156784913; API