Variant 16-28866144-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001387430.1(SH2B1):c.50C>A(p.Pro17Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000257 in 1,554,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Synonymous variant affecting the same amino acid position (i.e. P17P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SH2B1
NM_001387430.1 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.45

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06306204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B1	NM_001387430.1 linkuse as main transcript	c.50C>A	p.Pro17Gln	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.50C>A	p.Pro17Gln	missense_variant	1/8		NM_001387430.1	P3	Q9NRF2-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000126

AC:

AN:

158612

Hom.:

AF XY:

0.0000115

AC XY:

AN XY:

86838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000776

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:

0.00000214

AC:

AN:

1401952

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692658

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000810

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:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.0000113

ExAC

AF:

0.00000928

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

Jul 04, 2024

The SH2B1 c.50C>A variant is predicted to result in the amino acid substitution p.Pro17Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0078% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

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

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.064

MetaRNN

Benign

0.063

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

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

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.48

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

REVEL

Benign

0.060

Sift

Benign

0.090

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

Sift4G

Uncertain

0.034

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

Polyphen

0.77, 0.27

.;P;B;.;P;B;B

Vest4

0.39, 0.25, 0.38, 0.38, 0.37

MutPred

0.19

Loss of glycosylation at P17 (P = 0.0025);Loss of glycosylation at P17 (P = 0.0025);Loss of glycosylation at P17 (P = 0.0025);Loss of glycosylation at P17 (P = 0.0025);Loss of glycosylation at P17 (P = 0.0025);Loss of glycosylation at P17 (P = 0.0025);Loss of glycosylation at P17 (P = 0.0025);

MVP

0.068

MPC

0.41

ClinPred

0.32

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.041

gMVP

0.37

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