16-28866173-C-T

Position:

chr16-28866173-C-T

Variant summary

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

The NM_001387430.1(SH2B1):c.79C>T(p.Arg27Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,516,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SH2B1
NM_001387430.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.262

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=0.25074342).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B1	NM_001387430.1 linkuse as main transcript	c.79C>T	p.Arg27Trp	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.79C>T	p.Arg27Trp	missense_variant	1/8		NM_001387430.1	P3	Q9NRF2-1

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151316

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:

0.000198

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.0000955

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000428

AC:

AN:

163580

Hom.:

AF XY:

0.0000556

AC XY:

AN XY:

89866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000381

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000162

Gnomad SAS exome

AF:

0.0000414

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000306

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.0000286

AC:

AN:

1365306

Hom.:

Cov.:

AF XY:

0.0000340

AC XY:

AN XY:

675754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000325

Gnomad4 AMR exome

AF:

0.0000552

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000899

Gnomad4 SAS exome

AF:

0.0000374

Gnomad4 FIN exome

AF:

0.0000264

Gnomad4 NFE exome

AF:

0.0000254

Gnomad4 OTH exome

AF:

0.0000181

GnomAD4 genome

AF:

0.0000528

AC:

AN:

151424

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73992

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000198

Gnomad4 SAS

AF:

0.000210

Gnomad4 FIN

AF:

0.0000955

Gnomad4 NFE

AF:

0.0000590

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

SH2B1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

The SH2B1 c.79C>T variant is predicted to result in the amino acid substitution p.Arg27Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the SH2B1 protein (p.Arg27Trp). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SH2B1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

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

Eigen

Benign

0.028

Eigen_PC

Benign

0.071

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.25

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

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

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

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.3

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

REVEL

Benign

0.21

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D

Polyphen

0.99, 0.95

.;D;P;.;D;P;P

Vest4

0.49, 0.36, 0.49, 0.47, 0.48

MutPred

0.49

Loss of phosphorylation at S32 (P = 0.1218);Loss of phosphorylation at S32 (P = 0.1218);Loss of phosphorylation at S32 (P = 0.1218);Loss of phosphorylation at S32 (P = 0.1218);Loss of phosphorylation at S32 (P = 0.1218);Loss of phosphorylation at S32 (P = 0.1218);Loss of phosphorylation at S32 (P = 0.1218);

MVP

0.13

MPC

0.81

ClinPred

0.39

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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