dbSNP rs4788102: SH2B1:c.-171+330G>A (chr16-28862077-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001308293.2(SH2B1):c.-171+330G>A 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 151,972 control chromosomes in the GnomAD database, including 9,507 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 ( 9506 hom., cov: 32)

Exomes 𝑓: 0.38 ( 1 hom. )

Consequence

SH2B1
NM_001308293.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0810

Publications

80 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:

ENSG00000261766 (HGNC:):

ENSG00000261766 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B1	NM_001308293.2 link	c.-171+330G>A		intron_variant	Intron 2 of 10		NP_001295222.1	Q9NRF2-1A0A024QZD2B3KNV5
SH2B1	NM_001387404.1 link	c.-170-1591G>A		intron_variant	Intron 1 of 9		NP_001374333.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
SH2B1	ENST00000322610.12 link	c.-171+330G>A	intron_variant	Intron 2 of 10	2	ENSP00000321221.7	Q9NRF2-1
SH2B1	ENST00000563591.5 link	c.-170-1591G>A	intron_variant	Intron 1 of 2	2	ENSP00000458097.1	H3BVF6
SH2B1	ENST00000567536.5 link	c.-116+330G>A	intron_variant	Intron 2 of 3	3	ENSP00000455236.1	H3BPB4
ENSG00000261766	ENST00000567731.1 link	n.*89C>T	downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51700

AN:

151830

Hom.:

9477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.244

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.424

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.393

Gnomad OTH

AF:

0.306

GnomAD4 exome

AF:

0.375

AC:

AN:

Hom.:

AF XY:

0.444

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.341

AC:

51793

AN:

151948

Hom.:

9506

Cov.:

AF XY:

0.339

AC XY:

25188

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.263

AC:

10919

AN:

41460

American (AMR)

AF:

0.406

AC:

6199

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

928

AN:

3466

East Asian (EAS)

AF:

0.121

AC:

624

AN:

5164

South Asian (SAS)

AF:

0.218

AC:

1047

AN:

4812

European-Finnish (FIN)

AF:

0.424

AC:

4464

AN:

10526

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.393

AC:

26671

AN:

67944

Other (OTH)

AF:

0.310

AC:

654

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1721

3442

5162

6883

8604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<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:

0.365

Hom.:

18819

Bravo

AF:

0.338

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

-0.91

CADD

Benign

3.9

(source)

DANN

Benign

0.64

PhyloP100

-0.081

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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