chr12-111449855-A-G

Variant names:

• chr12-111449855-A-G
• rs739496
• NM_005475.3:c.*1553A>G

Variant summary

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

The NM_005475.3(SH2B3):​c.*1553A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,044 control chromosomes in the GnomAD database, including 7,093 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 0.27 (7091 hom., cov: 32)
  • Exomes 𝑓: 0.19 (2 hom.)
• Consequence: SH2B3 NM_005475.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• Publications: 57 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.*1553A>G		3_prime_UTR	Exon 8 of 8	NP_005466.1
	SH2B3	NM_001291424.1		c.*1553A>G		3_prime_UTR	Exon 7 of 7	NP_001278353.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.*1553A>G		3_prime_UTR	Exon 8 of 8	ENSP00000345492.2
	ATXN2	ENST00000642389.2		n.*170+1267T>C		intron	N/A	ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41601 AN: 151872 Hom.: 7095 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.897

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.194 AC: 12 AN: 62 Hom.: 2 Cov.: 0 AF XY: 0.217 AC XY: 10 AN XY: 46

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.146 AC: 7 AN: 48

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.274 AC: 41633 AN: 151982 Hom.: 7091 Cov.: 32 AF XY: 0.278 AC XY: 20620 AN XY: 74292

African (AFR) AF: 0.320 AC: 13257 AN: 41456

American (AMR) AF: 0.293 AC: 4467 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3466

East Asian (EAS) AF: 0.897 AC: 4638 AN: 5172

South Asian (SAS) AF: 0.372 AC: 1795 AN: 4824

European-Finnish (FIN) AF: 0.187 AC: 1965 AN: 10524

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.210 AC: 14267 AN: 67966

Other (OTH) AF: 0.292 AC: 615 AN: 2108

Alfa AF: 0.239 Hom.: 14964

Bravo AF: 0.289

Asia WGS AF: 0.546 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		0.22
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: rs739496; hg19: chr12-111887659;