1-156809396-G-T

Variant summary

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

The NM_003975.4(SH2D2A):​c.809C>A​(p.Ala270Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,316 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SH2D2A
NM_003975.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04
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=0.11596295).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SH2D2ANM_003975.4 linkuse as main transcriptc.809C>A p.Ala270Asp missense_variant 7/9 ENST00000368199.8 NP_003966.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SH2D2AENST00000368199.8 linkuse as main transcriptc.809C>A p.Ala270Asp missense_variant 7/91 NM_003975.4 ENSP00000357182 P2Q9NP31-1
SH2D2AENST00000392306.2 linkuse as main transcriptc.839C>A p.Ala280Asp missense_variant 7/91 ENSP00000376123 Q9NP31-2
SH2D2AENST00000368198.7 linkuse as main transcriptc.755C>A p.Ala252Asp missense_variant 7/91 ENSP00000357181 A2Q9NP31-4
SH2D2AENST00000468744.5 linkuse as main transcriptn.506C>A non_coding_transcript_exon_variant 3/32

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152198
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251164
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135752
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461646
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727126
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152316
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74476
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:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

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 GeneticsNov 08, 2022The c.839C>A (p.A280D) alteration is located in exon 7 (coding exon 7) of the SH2D2A gene. This alteration results from a C to A substitution at nucleotide position 839, causing the alanine (A) at amino acid position 280 to be replaced by an aspartic acid (D). 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
0.15
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
.;T;.
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.080
N
LIST_S2
Benign
0.67
T;T;T
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
.;L;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.7
N;N;N
REVEL
Benign
0.068
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
0.65, 0.76
.;P;P
Vest4
0.24
MutPred
0.097
.;Gain of ubiquitination at K274 (P = 0.107);.;
MVP
0.78
MPC
0.97
ClinPred
0.46
T
GERP RS
2.8
Varity_R
0.24
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs546031119; hg19: chr1-156779188; API