chr16-28866155-C-T

Variant names:

• chr16-28866155-C-T
• rs756529856
• NM_001387430.1:c.61C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001387430.1(SH2B1):​c.61C>T​(p.Pro21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,550,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P21P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.63
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06962067).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387430.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	NM_001387430.1	MANE Select	c.61C>T	p.Pro21Ser	missense	Exon 1 of 8	NP_001374359.1	Q9NRF2-1
	SH2B1	NM_001145795.2		c.61C>T	p.Pro21Ser	missense	Exon 2 of 9	NP_001139267.1	Q9NRF2-1
	SH2B1	NM_001308293.2		c.61C>T	p.Pro21Ser	missense	Exon 4 of 11	NP_001295222.1	Q9NRF2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	ENST00000684370.1	MANE Select	c.61C>T	p.Pro21Ser	missense	Exon 1 of 8	ENSP00000507475.1	Q9NRF2-1
	SH2B1	ENST00000618521.4	TSL:1	c.61C>T	p.Pro21Ser	missense	Exon 2 of 9	ENSP00000481709.1	Q9NRF2-1
	SH2B1	ENST00000359285.10	TSL:1	c.61C>T	p.Pro21Ser	missense	Exon 2 of 10	ENSP00000352232.5	Q9NRF2-3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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

GnomAD2 exomes AF: 0.0000526 AC: 8 AN: 151994 AF XY: 0.0000241

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000170

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.0000164 AC: 23 AN: 1398664 Hom.: 0 Cov.: 38 AF XY: 0.0000145 AC XY: 10 AN XY: 690772

African (AFR) AF: 0.00 AC: 0 AN: 31886

American (AMR) AF: 0.000274 AC: 10 AN: 36444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 36488

South Asian (SAS) AF: 0.00 AC: 0 AN: 79584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4178

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1081572

Other (OTH) AF: 0.0000173 AC: 1 AN: 57960

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.000393 AC: 6 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000284 Hom.: 0

ExAC AF: 0.00000911 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	SH2B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
PhyloP100		2.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.10
Sift	Benign	0.28	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.39
MutPred		0.30		Gain of phosphorylation at P21 (P = 0.0019)
MVP		0.14
MPC		0.86
ClinPred		0.097	T
GERP RS		2.8
PromoterAI		-0.0048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.044
gMVP		0.30
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756529856; hg19: chr16-28877476;