Variant 16-28866140-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001387430.1(SH2B1):c.46C>T(p.Pro16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,532,348 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 1 hom. )

Consequence

SH2B1
NM_001387430.1 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.17

Variant links:

Genes affected

SH2B1 (HGNC:30417): (SH2B adaptor protein 1) This gene encodes a member of the SH2-domain containing mediators family. The encoded protein mediates activation of various kinases and may function in cytokine and growth factor receptor signaling and cellular transformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

SH2B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0122437775).

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B1	NM_001387430.1 linkuse as main transcript	c.46C>T	p.Pro16Ser	missense_variant	1/8	ENST00000684370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B1	ENST00000684370.1 linkuse as main transcript	c.46C>T	p.Pro16Ser	missense_variant	1/8		NM_001387430.1	P3	Q9NRF2-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000484

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000584

AC:

AN:

154004

Hom.:

AF XY:

0.0000713

AC XY:

AN XY:

84106

show subpopulations

Gnomad AFR exome

AF:

0.000633

Gnomad AMR exome

AF:

0.000159

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

AF:

0.0000391

AC:

AN:

1380432

Hom.:

Cov.:

AF XY:

0.0000366

AC XY:

AN XY:

682136

show subpopulations

Gnomad4 AFR exome

AF:

0.000881

Gnomad4 AMR exome

AF:

0.000138

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:

0.00000748

Gnomad4 OTH exome

AF:

0.000123

GnomAD4 genome

AF:

0.000145

AC:

AN:

151916

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.000506

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000287

ExAC

AF:

0.0000373

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SH2B1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2024

The SH2B1 c.46C>T variant is predicted to result in the amino acid substitution p.Pro16Ser. To our knowledge, this variant has not been reported to be associated with obesity in the literature. It was detected in the heterozygous state in one lean control individual in an obesity study (Aerts et al. 2015. PubMed ID: 26031769). This variant is reported in 0.066% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;T;.;T;T;.;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.90

D;.;.;D;D;D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.012

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;N;.;N;N;N

MutationTaster

Benign

0.83

D;N;N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.47

N;N;N;N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.040

D;T;T;D;.;T;T

Sift4G

Pathogenic

0.0

D;T;T;D;T;T;T

Polyphen

0.0010, 1.0

.;B;D;.;B;D;D

Vest4

0.47, 0.32, 0.47, 0.44, 0.44

MVP

0.13

MPC

0.81

ClinPred

0.032

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.49

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over