rs2239194

Variant names:

• chr12-111445975-C-T
• rs2239194
• NM_005475.3:c.733-778C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005475.3(SH2B3):​c.733-778C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0717 in 152,340 control chromosomes in the GnomAD database, including 680 homozygotes. 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: 𝑓 0.072 (680 hom., cov: 33)
• Consequence: SH2B3 NM_005475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49
• Publications: 25 publications found

Genes affected

SH2B3 (HGNC:29605): (SH2B adaptor protein 3) This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ATXN2 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.733-778C>T		intron_variant	Intron 2 of 7	ENST00000341259.7	NP_005466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7	c.733-778C>T		intron_variant	Intron 2 of 7	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000538307.1	c.127-778C>T		intron_variant	Intron 1 of 6	2		ENSP00000440597.1
ATXN2	ENST00000642389.2	n.*171-1788G>A		intron_variant	Intron 26 of 26			ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10921 AN: 152222 Hom.: 679 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0779

Gnomad OTH AF: 0.0697

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0717 AC: 10922 AN: 152340 Hom.: 680 Cov.: 33 AF XY: 0.0752 AC XY: 5602 AN XY: 74484

African (AFR) AF: 0.0157 AC: 652 AN: 41592

American (AMR) AF: 0.0523 AC: 800 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.320 AC: 1654 AN: 5172

South Asian (SAS) AF: 0.201 AC: 972 AN: 4828

European-Finnish (FIN) AF: 0.113 AC: 1203 AN: 10610

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0780 AC: 5307 AN: 68034

Other (OTH) AF: 0.0704 AC: 149 AN: 2116

Alfa AF: 0.0763 Hom.: 1680

Bravo AF: 0.0656

Asia WGS AF: 0.254 AC: 881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.095
DANN	Benign	0.56
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2239194; hg19: chr12-111883779;