12-111446790-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005475.3(SH2B3):c.770T>C(p.Ile257Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,563,538 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I257V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 4 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.37

Publications

8 publications found

Variant links:

COSMIC-nc: COSV57983094

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]

SH2B3 links:

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]

ATXN2 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ATXN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008188218).

BP6

Variant 12-111446790-T-C is Benign according to our data. Variant chr12-111446790-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1336175.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (267/152272) while in subpopulation AFR AF = 0.00611 (254/41556). AF 95% confidence interval is 0.00549. There are 1 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3 link	c.770T>C	p.Ile257Thr	missense_variant	Exon 3 of 8	ENST00000341259.7	NP_005466.1	Q9UQQ2Q59H48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH2B3	ENST00000341259.7 link	c.770T>C	p.Ile257Thr	missense_variant	Exon 3 of 8	1	NM_005475.3	ENSP00000345492.2	Q9UQQ2
SH2B3	ENST00000538307.1 link	c.164T>C	p.Ile55Thr	missense_variant	Exon 2 of 7	2		ENSP00000440597.1	F5GYM4
ATXN2	ENST00000642389.2 link	n.*171-2603A>G		intron_variant	Intron 26 of 26			ENSP00000496055.2	A0A2R8Y7E6

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

265

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00608

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.00144

GnomAD2 exomes

AF:

0.000622

AC:

133

AN:

213838

AF XY:

0.000381

show subpopulations

Gnomad AFR exome

AF:

0.00706

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000777

GnomAD4 exome

AF:

0.000256

AC:

361

AN:

1411266

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

154

AN XY:

695090

show subpopulations

African (AFR)

AF:

0.00753

AC:

245

AN:

32522

American (AMR)

AF:

0.000392

AC:

AN:

40792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22484

East Asian (EAS)

AF:

0.00

AC:

AN:

39218

South Asian (SAS)

AF:

0.0000389

AC:

AN:

77192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51388

Middle Eastern (MID)

AF:

0.00309

AC:

AN:

5500

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1083962

Other (OTH)

AF:

0.000670

AC:

AN:

58208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00175

AC:

267

AN:

152272

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00611

AC:

254

AN:

41556

American (AMR)

AF:

0.000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000639

Hom.:

Bravo

AF:

0.00209

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000719

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Apr 06, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.079

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

7.4

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;D

Vest4

0.61

MVP

0.95

MPC

0.28

ClinPred

0.040

GERP RS

5.0

Varity_R

0.63

gMVP

0.78

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-111446790-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over