rs9972768

Variant names:

• chr16-28850413-A-C
• rs9972768
• NM_001308293.2:c.-301+3586A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001308293.2(SH2B1):​c.-301+3586A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 152,084 control chromosomes in the GnomAD database, including 9,529 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9529 hom., cov: 32)
• Consequence: SH2B1 NM_001308293.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347
• Publications: 25 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: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B1	NM_001308293.2	c.-301+3586A>C		intron_variant	Intron 1 of 10		NP_001295222.1
SH2B1	NM_001387404.1	c.-171+3586A>C		intron_variant	Intron 1 of 9		NP_001374333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B1	ENST00000322610.12	c.-301+3586A>C		intron_variant	Intron 1 of 10	2		ENSP00000321221.7
SH2B1	ENST00000563591.5	c.-171+3586A>C		intron_variant	Intron 1 of 2	2		ENSP00000458097.1
SH2B1	ENST00000567536.5	c.-246+3586A>C		intron_variant	Intron 1 of 3	3		ENSP00000455236.1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51812 AN: 151966 Hom.: 9500 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.307

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.341 AC: 51905 AN: 152084 Hom.: 9529 Cov.: 32 AF XY: 0.339 AC XY: 25240 AN XY: 74350

African (AFR) AF: 0.266 AC: 11011 AN: 41472

American (AMR) AF: 0.406 AC: 6197 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 930 AN: 3470

East Asian (EAS) AF: 0.121 AC: 626 AN: 5186

South Asian (SAS) AF: 0.218 AC: 1051 AN: 4824

European-Finnish (FIN) AF: 0.422 AC: 4466 AN: 10576

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26679 AN: 67966

Other (OTH) AF: 0.311 AC: 656 AN: 2112

Alfa AF: 0.372 Hom.: 12870

Bravo AF: 0.339

Asia WGS AF: 0.275 AC: 953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	4.8
DANN	Benign	0.38
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs9972768; hg19: chr16-28861734;