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12-111446804-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005475.3(SH2B3):c.784T>C(p.Trp262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,570,508 control chromosomes in the GnomAD database, including 282,793 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.68 ( 37727 hom., cov: 32)
Exomes 𝑓: 0.57 ( 245066 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.878
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.2047894E-6).
BP6
Variant 12-111446804-T-C is Benign according to our data. Variant chr12-111446804-T-C is described in ClinVar as [Benign]. Clinvar id is 1265448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SH2B3NM_005475.3 linkuse as main transcriptc.784T>C p.Trp262Arg missense_variant 3/8 ENST00000341259.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SH2B3ENST00000341259.7 linkuse as main transcriptc.784T>C p.Trp262Arg missense_variant 3/81 NM_005475.3 P1
SH2B3ENST00000538307.1 linkuse as main transcriptc.178T>C p.Trp60Arg missense_variant 2/72
ATXN2ENST00000642389.2 linkuse as main transcriptc.*171-2617A>G intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.676
AC:
102715
AN:
151964
Hom.:
37652
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.918
Gnomad AMI
AF:
0.543
Gnomad AMR
AF:
0.706
Gnomad ASJ
AF:
0.330
Gnomad EAS
AF:
0.998
Gnomad SAS
AF:
0.905
Gnomad FIN
AF:
0.602
Gnomad MID
AF:
0.627
Gnomad NFE
AF:
0.513
Gnomad OTH
AF:
0.647
GnomAD3 exomes
AF:
0.667
AC:
147137
AN:
220466
Hom.:
53297
AF XY:
0.661
AC XY:
77382
AN XY:
117014
show subpopulations
Gnomad AFR exome
AF:
0.931
Gnomad AMR exome
AF:
0.789
Gnomad ASJ exome
AF:
0.341
Gnomad EAS exome
AF:
0.999
Gnomad SAS exome
AF:
0.898
Gnomad FIN exome
AF:
0.603
Gnomad NFE exome
AF:
0.511
Gnomad OTH exome
AF:
0.601
GnomAD4 exome
AF:
0.571
AC:
809276
AN:
1418426
Hom.:
245066
Cov.:
36
AF XY:
0.577
AC XY:
403420
AN XY:
699524
show subpopulations
Gnomad4 AFR exome
AF:
0.935
Gnomad4 AMR exome
AF:
0.774
Gnomad4 ASJ exome
AF:
0.349
Gnomad4 EAS exome
AF:
0.999
Gnomad4 SAS exome
AF:
0.892
Gnomad4 FIN exome
AF:
0.599
Gnomad4 NFE exome
AF:
0.514
Gnomad4 OTH exome
AF:
0.598
GnomAD4 genome
AF:
0.676
AC:
102854
AN:
152082
Hom.:
37727
Cov.:
32
AF XY:
0.688
AC XY:
51173
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.918
Gnomad4 AMR
AF:
0.707
Gnomad4 ASJ
AF:
0.330
Gnomad4 EAS
AF:
0.998
Gnomad4 SAS
AF:
0.905
Gnomad4 FIN
AF:
0.602
Gnomad4 NFE
AF:
0.513
Gnomad4 OTH
AF:
0.650
Alfa
AF:
0.544
Hom.:
52514
Bravo
AF:
0.690
TwinsUK
AF:
0.509
AC:
1889
ALSPAC
AF:
0.550
AC:
2118
ESP6500AA
AF:
0.906
AC:
3992
ESP6500EA
AF:
0.495
AC:
4254
ExAC
AF:
0.662
AC:
79944
Asia WGS
AF:
0.943
AC:
3277
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 30, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 10, 2019This variant is associated with the following publications: (PMID: 26553438, 28628107, 29547645, 21909115, 26621817, 18311140, 20546165, 23222517, 24777453, 19820697, 19198610, 17554260, 24026423, 24482502, 20560212) -
Primary myelofibrosis;C3277671:Thrombocythemia 1;C4551637:Primary familial polycythemia due to EPO receptor mutation Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 16, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.048
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.57
Cadd
Benign
13
Dann
Benign
0.24
DEOGEN2
Benign
0.25
T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.077
N
LIST_S2
Benign
0.0068
T;T
MetaRNN
Benign
0.0000012
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-2.3
N;.
MutationTaster
Benign
1.0
P;P;P
PrimateAI
Benign
0.33
T
PROVEAN
Benign
4.2
N;N
REVEL
Benign
0.16
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;B
Vest4
0.040
MutPred
0.15
Gain of disorder (P = 0.0048);.;
MPC
0.11
ClinPred
0.0019
T
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs3184504; hg19: chr12-111884608; COSMIC: COSV57981059; COSMIC: COSV57981059; API