chr16-28872006-T-C

Variant names:

• chr16-28872006-T-C
• rs28433345
• NM_001387430.1:c.1513+23T>C

Variant summary

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

The NM_001387430.1(SH2B1):​c.1513+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,489,392 control chromosomes in the GnomAD database, including 331,705 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 0.68 (35327 hom., cov: 30)
  • Exomes 𝑓: 0.66 (296378 hom.)
• Consequence: SH2B1 NM_001387430.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.412
• Publications: 15 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=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B1	NM_001387430.1	c.1513+23T>C		intron_variant	Intron 5 of 7	ENST00000684370.1	NP_001374359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B1	ENST00000684370.1	c.1513+23T>C		intron_variant	Intron 5 of 7		NM_001387430.1	ENSP00000507475.1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103018 AN: 151776 Hom.: 35264 Cov.: 30

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.654

GnomAD2 exomes AF: 0.691 AC: 170918 AN: 247440 AF XY: 0.692

Gnomad AFR exome AF: 0.742

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.716

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.638

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.662 AC: 885498 AN: 1337498 Hom.: 296378 Cov.: 22 AF XY: 0.667 AC XY: 448406 AN XY: 672028

African (AFR) AF: 0.741 AC: 22977 AN: 31016

American (AMR) AF: 0.787 AC: 34899 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 14764 AN: 25336

East Asian (EAS) AF: 0.711 AC: 27843 AN: 39178

South Asian (SAS) AF: 0.849 AC: 71197 AN: 83818

European-Finnish (FIN) AF: 0.567 AC: 30277 AN: 53352

Middle Eastern (MID) AF: 0.649 AC: 2986 AN: 4600

European-Non Finnish (NFE) AF: 0.643 AC: 642858 AN: 999644

Other (OTH) AF: 0.670 AC: 37697 AN: 56226

GnomAD4 genome AF: 0.679 AC: 103141 AN: 151894 Hom.: 35327 Cov.: 30 AF XY: 0.681 AC XY: 50540 AN XY: 74214

African (AFR) AF: 0.738 AC: 30570 AN: 41444

American (AMR) AF: 0.716 AC: 10922 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2027 AN: 3466

East Asian (EAS) AF: 0.712 AC: 3658 AN: 5140

South Asian (SAS) AF: 0.860 AC: 4145 AN: 4818

European-Finnish (FIN) AF: 0.569 AC: 6000 AN: 10552

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43729 AN: 67902

Other (OTH) AF: 0.658 AC: 1386 AN: 2106

Alfa AF: 0.654 Hom.: 12787

Bravo AF: 0.689

Asia WGS AF: 0.818 AC: 2839 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.5
DANN	Benign	0.76
PhyloP100		-0.41
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28433345; hg19: chr16-28883327; COSMIC: COSV59466153; COSMIC: COSV59466153;