chr12-111447547-A-ATGGGGTGGGG

Variant names:

• chr12-111447547-A-ATGGGGTGGGG
• rs111340708
• NM_005475.3:c.1236+19_1236+28dupTGGGGTGGGG

Variant summary

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

The NM_005475.3(SH2B3):​c.1236+19_1236+28dupTGGGGTGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000098 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2B3 NM_005475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80
• Publications: 7 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.1236+19_1236+28dupTGGGGTGGGG		intron_variant	Intron 6 of 7	ENST00000341259.7	NP_005466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7	c.1236+3_1236+4insTGGGGTGGGG		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000538307.1	c.630+3_630+4insTGGGGTGGGG		splice_region_variant, intron_variant	Intron 5 of 6	2		ENSP00000440597.1
ATXN2	ENST00000642389.2	n.*171-3361_*171-3360insCCCCACCCCA		intron_variant	Intron 26 of 26			ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.0000894 AC: 8 AN: 89446 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000983 AC: 49 AN: 498316 Hom.: 0 Cov.: 0 AF XY: 0.0000728 AC XY: 19 AN XY: 261152

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

American (AMR) AF: 0.0000765 AC: 2 AN: 26138

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35510

South Asian (SAS) AF: 0.0000750 AC: 4 AN: 53318

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

Middle Eastern (MID) AF: 0.000292 AC: 1 AN: 3422

European-Non Finnish (NFE) AF: 0.000130 AC: 39 AN: 299086

Other (OTH) AF: 0.000126 AC: 3 AN: 23724

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000894 AC: 8 AN: 89446 Hom.: 0 Cov.: 0 AF XY: 0.0000708 AC XY: 3 AN XY: 42374

African (AFR) AF: 0.0000324 AC: 1 AN: 30892

American (AMR) AF: 0.000120 AC: 1 AN: 8304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1608

East Asian (EAS) AF: 0.00 AC: 0 AN: 4278

South Asian (SAS) AF: 0.00 AC: 0 AN: 2724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.000165 AC: 6 AN: 36436

Other (OTH) AF: 0.00 AC: 0 AN: 1212

Alfa AF: 0.00 Hom.: 272

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;