chr16-28866157-C-T

Variant names:

• chr16-28866157-C-T
• rs778108707
• NM_001387430.1:c.63C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001387430.1(SH2B1):​c.63C>T​(p.Pro21Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,552,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SH2B1 NM_001387430.1 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.32
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-28866157-C-T is Benign according to our data. Variant chr16-28866157-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3054971.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 16 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.63C>T	p.Pro21Pro	synonymous	Exon 1 of 8	NP_001374359.1	Q9NRF2-1
	SH2B1	NM_001145795.2		c.63C>T	p.Pro21Pro	synonymous	Exon 2 of 9	NP_001139267.1	Q9NRF2-1
	SH2B1	NM_001308293.2		c.63C>T	p.Pro21Pro	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.63C>T	p.Pro21Pro	synonymous	Exon 1 of 8	ENSP00000507475.1	Q9NRF2-1
	SH2B1	ENST00000618521.4	TSL:1	c.63C>T	p.Pro21Pro	synonymous	Exon 2 of 9	ENSP00000481709.1	Q9NRF2-1
	SH2B1	ENST00000359285.10	TSL:1	c.63C>T	p.Pro21Pro	synonymous	Exon 2 of 10	ENSP00000352232.5	Q9NRF2-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000131 AC: 2 AN: 152850 AF XY: 0.0000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.0000114 AC: 16 AN: 1400032 Hom.: 0 Cov.: 38 AF XY: 0.0000116 AC XY: 8 AN XY: 691440

African (AFR) AF: 0.00 AC: 0 AN: 31898

American (AMR) AF: 0.00 AC: 0 AN: 36548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 36486

South Asian (SAS) AF: 0.00 AC: 0 AN: 79654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4214

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1082418

Other (OTH) AF: 0.0000345 AC: 2 AN: 57992

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

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

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SH2B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.1
DANN	Benign	0.90
PhyloP100		-1.3
PromoterAI		0.0042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs778108707; hg19: chr16-28877478;