16-28866154-A-C

Position:

• chr16-28866154-A-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001387430.1(SH2B1):​c.60A>C​(p.Pro20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 64,356 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0042 (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: -1.11

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-28866154-A-C is Benign according to our data. Variant chr16-28866154-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 791647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BS2: High AC in GnomAd4 at 403 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B1	NM_001387430.1	c.60A>C	p.Pro20=	synonymous_variant	1/8	ENST00000684370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B1	ENST00000684370.1	c.60A>C	p.Pro20=	synonymous_variant	1/8		NM_001387430.1	P3

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 401 AN: 64320 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.0194

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00609

Gnomad EAS AF: 0.00401

Gnomad SAS AF: 0.00535

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00629

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00424 AC: 3759 AN: 887338 Hom.: 0 Cov.: 35 AF XY: 0.00456 AC XY: 1984 AN XY: 435538

Gnomad4 AFR exome AF: 0.00303

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.0119

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00621

GnomAD4 genome AF: 0.00626 AC: 403 AN: 64356 Hom.: 0 Cov.: 21 AF XY: 0.00609 AC XY: 197 AN XY: 32324

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00609

Gnomad4 EAS AF: 0.00401

Gnomad4 SAS AF: 0.00594

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.00553

Gnomad4 OTH AF: 0.00622

Alfa AF: 0.0921 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

SH2B1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 09, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1355653845; hg19: chr16-28877475;