NM_001387430.1:c.66G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001387430.1(SH2B1):​c.66G>C​(p.Pro22Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 0.000017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2B1 NM_001387430.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-28866160-G-C is Benign according to our data. Variant chr16-28866160-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 765123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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>C	p.Pro22Pro	synonymous	Exon 1 of 8	NP_001374359.1	Q9NRF2-1
	SH2B1	NM_001145795.2		c.66G>C	p.Pro22Pro	synonymous	Exon 2 of 9	NP_001139267.1	Q9NRF2-1
	SH2B1	NM_001308293.2		c.66G>C	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>C	p.Pro22Pro	synonymous	Exon 1 of 8	ENSP00000507475.1	Q9NRF2-1
	SH2B1	ENST00000618521.4	TSL:1	c.66G>C	p.Pro22Pro	synonymous	Exon 2 of 9	ENSP00000481709.1	Q9NRF2-1
	SH2B1	ENST00000359285.10	TSL:1	c.66G>C	p.Pro22Pro	synonymous	Exon 2 of 10	ENSP00000352232.5	Q9NRF2-3

Frequencies

GnomAD3 genomes AF: 0.0000173 AC: 2 AN: 115410 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000318

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: 0.000149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000425 AC: 50 AN: 117746 AF XY: 0.000382

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000198

Gnomad ASJ exome AF: 0.000317

Gnomad EAS exome AF: 0.000372

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.000319

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00219 AC: 1689 AN: 772810 Hom.: 0 Cov.: 35 AF XY: 0.00228 AC XY: 875 AN XY: 383662

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

African (AFR) AF: 0.00115 AC: 21 AN: 18302

American (AMR) AF: 0.00427 AC: 78 AN: 18280

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 56 AN: 12150

East Asian (EAS) AF: 0.00377 AC: 45 AN: 11938

South Asian (SAS) AF: 0.00469 AC: 242 AN: 51624

European-Finnish (FIN) AF: 0.00514 AC: 106 AN: 20614

Middle Eastern (MID) AF: 0.00143 AC: 3 AN: 2104

European-Non Finnish (NFE) AF: 0.00170 AC: 1033 AN: 608604

Other (OTH) AF: 0.00360 AC: 105 AN: 29194

⚠️ 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: 0.0000173 AC: 2 AN: 115464 Hom.: 0 Cov.: 30 AF XY: 0.0000353 AC XY: 2 AN XY: 56654

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

African (AFR) AF: 0.0000318 AC: 1 AN: 31460

American (AMR) AF: 0.00 AC: 0 AN: 12200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2842

East Asian (EAS) AF: 0.00 AC: 0 AN: 3508

South Asian (SAS) AF: 0.00 AC: 0 AN: 3046

European-Finnish (FIN) AF: 0.000149 AC: 1 AN: 6734

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53174

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), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	SH2B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.81
PhyloP100		0.21
PromoterAI		0.023	Neutral
Mutation Taster		=100/0	polymorphism

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;