dbSNP rs62037368: SH2B1:c.1726-40G>A (chr16-28872494-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.85

Publications

2 publications found

Variant links:

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

SH2B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B1	NM_001387430.1 link	c.1726-40G>A		intron_variant	Intron 6 of 7	ENST00000684370.1	NP_001374359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B1	ENST00000684370.1 link	c.1726-40G>A		intron_variant	Intron 6 of 7		NM_001387430.1	ENSP00000507475.1		Q9NRF2-1

Frequencies

GnomAD3 genomes

AF:

0.00831

AC:

1265

AN:

152136

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0116

AC XY:

8239

AN XY:

710612

show subpopulations

African (AFR)

AF:

0.00214

AC:

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:

AN:

39452

South Asian (SAS)

AF:

0.000919

AC:

AN:

81572

European-Finnish (FIN)

AF:

0.0123

AC:

643

AN:

52314

Middle Eastern (MID)

AF:

0.000531

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.0142

AC:

15560

AN:

1096140

Other (OTH)

AF:

0.0103

AC:

609

AN:

59278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

910

1821

2731

3642

4552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00832

AC:

1266

AN:

152252

Hom.:

Cov.:

AF XY:

0.00837

AC XY:

623

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41544

American (AMR)

AF:

0.00268

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0194

AC:

206

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0131

AC:

888

AN:

67998

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00708

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.9

(source)

DANN

Benign

0.78

PhyloP100

1.8

PromoterAI

-0.039

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over