12-111447547-ATGGGGTGGGGTGGGG-ATGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant names:

• chr12-111447547-A-ATGGGGTGGGGTGGGG
• rs111340708
• NM_005475.3:c.1236+14_1236+28dupTGGGGTGGGGTGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000341259.7(SH2B3):​c.1236+3_1236+4insTGGGGTGGGGTGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000060 (1 hom.)
• Consequence: SH2B3 ENST00000341259.7 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000341259.7. 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
	SH2B3	NM_005475.3	MANE Select	c.1236+14_1236+28dupTGGGGTGGGGTGGGG		intron	N/A	NP_005466.1	Q9UQQ2
	SH2B3	NM_001291424.1		c.630+14_630+28dupTGGGGTGGGGTGGGG		intron	N/A	NP_001278353.1	B7Z7K6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.1236+3_1236+4insTGGGGTGGGGTGGGG		splice_region intron	N/A	ENSP00000345492.2	Q9UQQ2
	SH2B3	ENST00000896496.1		c.1239+3_1239+4insTGGGGTGGGGTGGGG		splice_region intron	N/A	ENSP00000566555.1
	SH2B3	ENST00000935782.1		c.1239+3_1239+4insTGGGGTGGGGTGGGG		splice_region intron	N/A	ENSP00000605841.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000602 AC: 3 AN: 498322 Hom.: 1 Cov.: 0 AF XY: 0.00000766 AC XY: 2 AN XY: 261154

African (AFR) AF: 0.00 AC: 0 AN: 19554

American (AMR) AF: 0.00 AC: 0 AN: 26140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9094

East Asian (EAS) AF: 0.0000563 AC: 2 AN: 35510

South Asian (SAS) AF: 0.0000188 AC: 1 AN: 53320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 299088

Other (OTH) AF: 0.00 AC: 0 AN: 23724

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111340708; hg19: chr12-111885351;