16-28866173-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.262

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25074342).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000595 AC: 9 AN: 151316 Hom.: 0 Cov.: 32

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: 7 AN: 163580 Hom.: 0 AF XY: 0.0000556 AC XY: 5 AN XY: 89866

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: 39 AN: 1365306 Hom.: 0 Cov.: 37 AF XY: 0.0000340 AC XY: 23 AN XY: 675754

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: 8 AN: 151424 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73992

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.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	26
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	D
LIST_S2	Uncertain	0.96	D;.;.;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;.;D;D
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	T
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

Other links and lift over

dbSNP: rs933512684; hg19: chr16-28877494;