Genetic Variant SH2B1:c.*518C>T (chr16-28874338-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001387430.1(SH2B1):c.*518C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 152,592 control chromosomes in the GnomAD database, including 7,988 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 0.28 ( 7975 hom., cov: 33)

Exomes 𝑓: 0.28 ( 13 hom. )

Consequence

SH2B1
NM_001387430.1 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.29

Publications

153 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:

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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=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SH2B1	NM_001387430.1	MANE Select	c.*518C>T	downstream_gene	N/A	NP_001374359.1
SH2B1	NM_001145795.2		c.*518C>T	downstream_gene	N/A	NP_001139267.1
SH2B1	NM_001308293.2		c.*518C>T	downstream_gene	N/A	NP_001295222.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SH2B1	ENST00000684370.1	MANE Select	c.*518C>T	downstream_gene	N/A	ENSP00000507475.1
SH2B1	ENST00000618521.4	TSL:1	c.*518C>T	downstream_gene	N/A	ENSP00000481709.1
SH2B1	ENST00000359285.10	TSL:1	c.*890C>T	downstream_gene	N/A	ENSP00000352232.5

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43257

AN:

152110

Hom.:

7963

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0724

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.383

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.422

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.391

Gnomad OTH

AF:

0.271

GnomAD4 exome

AF:

0.277

AC:

101

AN:

364

Hom.:

AF XY:

0.292

AC XY:

AN XY:

216

show subpopulations

African (AFR)

AF:

0.107

AC:

AN:

American (AMR)

AF:

0.429

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

AN:

East Asian (EAS)

AF:

0.250

AC:

AN:

South Asian (SAS)

AF:

0.100

AC:

AN:

European-Finnish (FIN)

AF:

0.429

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.305

AC:

AN:

220

Other (OTH)

AF:

0.188

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.284

AC:

43278

AN:

152228

Hom.:

7975

Cov.:

AF XY:

0.284

AC XY:

21123

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0722

AC:

3000

AN:

41562

American (AMR)

AF:

0.384

AC:

5883

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

929

AN:

3470

East Asian (EAS)

AF:

0.112

AC:

578

AN:

5170

South Asian (SAS)

AF:

0.202

AC:

973

AN:

4828

European-Finnish (FIN)

AF:

0.422

AC:

4475

AN:

10592

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.391

AC:

26581

AN:

67980

Other (OTH)

AF:

0.272

AC:

574

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1462

2923

4385

5846

7308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<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:

0.350

Hom.:

29214

Bravo

AF:

0.274

Asia WGS

AF:

0.212

AC:

736

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.2

(source)

DANN

Benign

0.44

PhyloP100

-1.3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over