16-28866110-T-C

Position:

• chr16-28866110-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001387430.1(SH2B1):​c.16T>C​(p.Ser6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.0650

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06502324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B1	NM_001387430.1	c.16T>C	p.Ser6Pro	missense_variant	1/8	ENST00000684370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B1	ENST00000684370.1	c.16T>C	p.Ser6Pro	missense_variant	1/8		NM_001387430.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426016 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706684

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: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SH2B1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The SH2B1 c.16T>C variant is predicted to result in the amino acid substitution p.Ser6Pro. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0056	T;T;.;T;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.68	T;.;.;T;T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.065	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.12	.;N;N;.;N;N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.90	N;N;N;N;.;N;N
REVEL	Benign	0.073
Sift	Benign	0.12	T;T;T;T;.;T;T
Sift4G	Pathogenic	0.0	D;T;T;D;T;T;T
Polyphen		0.0020, 0.0030	.;B;B;.;B;B;B
Vest4		0.35, 0.25, 0.33, 0.34
MutPred		0.23		Loss of phosphorylation at S6 (P = 0.0018);Loss of phosphorylation at S6 (P = 0.0018);Loss of phosphorylation at S6 (P = 0.0018);Loss of phosphorylation at S6 (P = 0.0018);Loss of phosphorylation at S6 (P = 0.0018);Loss of phosphorylation at S6 (P = 0.0018);Loss of phosphorylation at S6 (P = 0.0018);
MVP		0.26
MPC		0.60
ClinPred		0.16	T
GERP RS		0.61
Varity_R		0.088
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1401942551; hg19: chr16-28877431;