16-28866159-C-T

Variant names:

• chr16-28866159-C-T
• rs749598219
• NM_001387430.1:c.65C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001387430.1(SH2B1):​c.65C>T​(p.Pro22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,400,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.716

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14591399).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B1	NM_001387430.1	c.65C>T	p.Pro22Leu	missense_variant	Exon 1 of 8	ENST00000684370.1	NP_001374359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B1	ENST00000684370.1	c.65C>T	p.Pro22Leu	missense_variant	Exon 1 of 8		NM_001387430.1	ENSP00000507475.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1400272 Hom.: 0 Cov.: 38 AF XY: 0.0000159 AC XY: 11 AN XY: 691606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000157

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;.;T;T;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T;.;.;T;T;T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;L;.;L;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N;N;N;N;.;N;N
REVEL	Benign	0.072
Sift	Uncertain	0.0040	D;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;T;T;D;T;T;T
Polyphen		0.0030, 0.0020	.;B;B;.;B;B;B
Vest4		0.42, 0.34, 0.42, 0.41, 0.42
MutPred		0.23		Loss of glycosylation at P22 (P = 4e-04);Loss of glycosylation at P22 (P = 4e-04);Loss of glycosylation at P22 (P = 4e-04);Loss of glycosylation at P22 (P = 4e-04);Loss of glycosylation at P22 (P = 4e-04);Loss of glycosylation at P22 (P = 4e-04);Loss of glycosylation at P22 (P = 4e-04);
MVP		0.18
MPC		0.87
ClinPred		0.75	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.069
gMVP		0.45

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: rs749598219; hg19: chr16-28877480; COSMIC: COSV59467430; COSMIC: COSV59467430;