rs945365382

Variant names:

• chr16-28866160-G-A
• rs945365382
• NM_001387430.1:c.66G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-28866160-G-A
• chr16-28866160-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001387430.1(SH2B1):​c.66G>A​(p.Pro22Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 780,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P22P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000043 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2B1 NM_001387430.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.206
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 16-28866160-G-A is Benign according to our data. Variant chr16-28866160-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2721116.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.206 with no splicing effect.

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.66G>A	p.Pro22Pro	synonymous	Exon 1 of 8	NP_001374359.1	Q9NRF2-1
	SH2B1	NM_001145795.2		c.66G>A	p.Pro22Pro	synonymous	Exon 2 of 9	NP_001139267.1	Q9NRF2-1
	SH2B1	NM_001308293.2		c.66G>A	p.Pro22Pro	synonymous	Exon 4 of 11	NP_001295222.1	Q9NRF2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	ENST00000684370.1	MANE Select	c.66G>A	p.Pro22Pro	synonymous	Exon 1 of 8	ENSP00000507475.1	Q9NRF2-1
	SH2B1	ENST00000618521.4	TSL:1	c.66G>A	p.Pro22Pro	synonymous	Exon 2 of 9	ENSP00000481709.1	Q9NRF2-1
	SH2B1	ENST00000359285.10	TSL:1	c.66G>A	p.Pro22Pro	synonymous	Exon 2 of 10	ENSP00000352232.5	Q9NRF2-3

Frequencies

GnomAD3 genomes AF: 0.0000433 AC: 5 AN: 115466 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000636

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 96 AN: 780668 Hom.: 0 Cov.: 35 AF XY: 0.000108 AC XY: 42 AN XY: 387826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18470

American (AMR) AF: 0.00 AC: 0 AN: 18594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12416

East Asian (EAS) AF: 0.00 AC: 0 AN: 12362

South Asian (SAS) AF: 0.00 AC: 0 AN: 52480

European-Finnish (FIN) AF: 0.0000476 AC: 1 AN: 21000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2134

European-Non Finnish (NFE) AF: 0.000153 AC: 94 AN: 613562

Other (OTH) AF: 0.0000337 AC: 1 AN: 29650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000433 AC: 5 AN: 115522 Hom.: 0 Cov.: 30 AF XY: 0.0000176 AC XY: 1 AN XY: 56678

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000635 AC: 2 AN: 31480

American (AMR) AF: 0.00 AC: 0 AN: 12206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2846

East Asian (EAS) AF: 0.00 AC: 0 AN: 3512

South Asian (SAS) AF: 0.00 AC: 0 AN: 3048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53186

Other (OTH) AF: 0.00 AC: 0 AN: 1612

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00192603), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000304 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	SH2B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.7
DANN	Benign	0.91
PhyloP100		0.21
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs945365382; hg19: chr16-28877481;