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GeneBe

12-111446814-G-A

Variant summary

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

The NM_005475.3(SH2B3):c.794G>A(p.Arg265Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,581,586 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R265R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21
Variant links:
Genes affected
SH2B3 (HGNC:29605): (SH2B adaptor protein 3) This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]
ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

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=0.17018974).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SH2B3NM_005475.3 linkuse as main transcriptc.794G>A p.Arg265Gln missense_variant 3/8 ENST00000341259.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SH2B3ENST00000341259.7 linkuse as main transcriptc.794G>A p.Arg265Gln missense_variant 3/81 NM_005475.3 P1
SH2B3ENST00000538307.1 linkuse as main transcriptc.188G>A p.Arg63Gln missense_variant 2/72
ATXN2ENST00000642389.2 linkuse as main transcriptc.*171-2627C>T intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000315
AC:
48
AN:
152154
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000140
AC:
32
AN:
227774
Hom.:
1
AF XY:
0.000132
AC XY:
16
AN XY:
121414
show subpopulations
Gnomad AFR exome
AF:
0.000499
Gnomad AMR exome
AF:
0.000303
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:
0.000136
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000260
AC:
371
AN:
1429432
Hom.:
1
Cov.:
33
AF XY:
0.000269
AC XY:
190
AN XY:
706338
show subpopulations
Gnomad4 AFR exome
AF:
0.000666
Gnomad4 AMR exome
AF:
0.000255
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000124
Gnomad4 FIN exome
AF:
0.0000192
Gnomad4 NFE exome
AF:
0.000295
Gnomad4 OTH exome
AF:
0.000237
GnomAD4 genome
AF:
0.000315
AC:
48
AN:
152154
Hom.:
0
Cov.:
31
AF XY:
0.000283
AC XY:
21
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.000579
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000241
Hom.:
0
Bravo
AF:
0.000325
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000124
AC:
15

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 testingMendelicsMay 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.33
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;.
Eigen
Benign
0.17
Eigen_PC
Benign
0.091
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.083
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.24
Sift
Benign
0.24
T;T
Sift4G
Benign
0.093
T;T
Polyphen
1.0
D;D
Vest4
0.30
MVP
0.92
MPC
0.41
ClinPred
0.062
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.085
gMVP
0.43

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

LitVar

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

Other links and lift over

dbSNP: rs149554298; hg19: chr12-111884618; COSMIC: COSV57985043; COSMIC: COSV57985043; API