rs62037368

Variant names:

• chr16-28872494-G-A
• rs62037368
• NM_001387430.1:c.1726-40G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001387430.1(SH2B1):​c.1726-40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,587,946 control chromosomes in the GnomAD database, including 136 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 0.0083 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (127 hom.)
• Consequence: SH2B1 NM_001387430.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High AC in GnomAd4 at 1266 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.1726-40G>A		intron	N/A	NP_001374359.1	Q9NRF2-1
	SH2B1	NM_001145795.2		c.1726-40G>A		intron	N/A	NP_001139267.1	Q9NRF2-1
	SH2B1	NM_001308293.2		c.1726-40G>A		intron	N/A	NP_001295222.1	Q9NRF2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	ENST00000684370.1	MANE Select	c.1726-40G>A		intron	N/A	ENSP00000507475.1	Q9NRF2-1
	SH2B1	ENST00000618521.4	TSL:1	c.1726-40G>A		intron	N/A	ENSP00000481709.1	Q9NRF2-1
	SH2B1	ENST00000359285.10	TSL:1	c.1726-40G>A		intron	N/A	ENSP00000352232.5	Q9NRF2-3

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1265 AN: 152136 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00794 AC: 1852 AN: 233304 AF XY: 0.00809

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00471

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00806

GnomAD4 exome AF: 0.0120 AC: 17190 AN: 1435694 Hom.: 127 Cov.: 32 AF XY: 0.0116 AC XY: 8239 AN XY: 710612

African (AFR) AF: 0.00214 AC: 71 AN: 33190

American (AMR) AF: 0.00251 AC: 110 AN: 43832

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 119 AN: 24270

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.000919 AC: 75 AN: 81572

European-Finnish (FIN) AF: 0.0123 AC: 643 AN: 52314

Middle Eastern (MID) AF: 0.000531 AC: 3 AN: 5646

European-Non Finnish (NFE) AF: 0.0142 AC: 15560 AN: 1096140

Other (OTH) AF: 0.0103 AC: 609 AN: 59278

GnomAD4 genome AF: 0.00832 AC: 1266 AN: 152252 Hom.: 9 Cov.: 33 AF XY: 0.00837 AC XY: 623 AN XY: 74460

African (AFR) AF: 0.00250 AC: 104 AN: 41544

American (AMR) AF: 0.00268 AC: 41 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 888 AN: 67998

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.0101 Hom.: 4

Bravo AF: 0.00708

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		1.8
PromoterAI		-0.039	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs62037368; hg19: chr16-28883815;