16-28866159-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001387430.1(SH2B1):c.65C>A(p.Pro22Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,552,354 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 1 hom. )

Consequence

SH2B1
NM_001387430.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.716

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11972839).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B1	NM_001387430.1 link	c.65C>A	p.Pro22Gln	missense_variant	Exon 1 of 8	ENST00000684370.1	NP_001374359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B1	ENST00000684370.1 link	c.65C>A	p.Pro22Gln	missense_variant	Exon 1 of 8		NM_001387430.1	ENSP00000507475.1		Q9NRF2-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000655

AC:

AN:

152646

Hom.:

AF XY:

0.0000839

AC XY:

AN XY:

83392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000160

Gnomad ASJ exome

AF:

0.000122

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000434

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000507

Gnomad OTH exome

AF:

0.000235

GnomAD4 exome

AF:

0.0000407

AC:

AN:

1400272

Hom.:

Cov.:

AF XY:

0.0000463

AC XY:

AN XY:

691606

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000164

Gnomad4 ASJ exome

AF:

0.0000799

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000286

Gnomad4 OTH exome

AF:

0.000224

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

ExAC

AF:

0.00000899

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>A (p.P22Q) alteration is located in exon 2 (coding exon 1) of the SH2B1 gene. This alteration results from a C to A substitution at nucleotide position 65, causing the proline (P) at amino acid position 22 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SH2B1-related disorder

Uncertain:1

Apr 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SH2B1 c.65C>A variant is predicted to result in the amino acid substitution p.Pro22Gln. This variant has been reported as compound heterozygous with c.806G>T (p.Gly269Val) of uncertain significance in a Palestinian individual with severe early-onset obesity (case P30 on Table 3, Mohammed et al. 2023. PubMed ID: 37329217). This variant is reported in 0.015% of alleles in individuals of Latino descent in gnomAD V2. However, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.11% (5/4568) in individuals of Middle Eastern ancestry including one homozygous. 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

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

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

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.076

MetaRNN

Benign

0.12

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

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.5

.;L;L;.;L;L;L

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.045

Sift

Uncertain

0.0040

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.62, 0.44

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

Vest4

0.43, 0.32, 0.44, 0.42, 0.43

MVP

0.14

MPC

0.83

ClinPred

0.074

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.086

gMVP

0.45

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

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