12-111446611-T-C

Variant names:

• chr12-111446611-T-C
• rs28362508
• NM_005475.3:c.733-142T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005475.3(SH2B3):​c.733-142T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 565,604 control chromosomes in the GnomAD database, including 12,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3042 hom., cov: 32)
  • Exomes 𝑓: 0.21 (9515 hom.)
• Consequence: SH2B3 NM_005475.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.277
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-111446611-T-C is Benign according to our data. Variant chr12-111446611-T-C is described in ClinVar as [Benign]. Clinvar id is 1281022.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.733-142T>C		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.733-142T>C		intron_variant	Intron 2 of 7	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000538307.1	c.127-142T>C		intron_variant	Intron 1 of 6	2		ENSP00000440597.1
ATXN2	ENST00000642389.2	n.*171-2424A>G		intron_variant	Intron 26 of 26			ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29673 AN: 151972 Hom.: 3041 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.207 AC: 85637 AN: 413514 Hom.: 9515 AF XY: 0.209 AC XY: 45085 AN XY: 215320

African (AFR) AF: 0.160 AC: 1873 AN: 11670

American (AMR) AF: 0.158 AC: 2381 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 1326 AN: 12730

East Asian (EAS) AF: 0.280 AC: 7991 AN: 28518

South Asian (SAS) AF: 0.273 AC: 9909 AN: 36332

European-Finnish (FIN) AF: 0.187 AC: 6172 AN: 33072

Middle Eastern (MID) AF: 0.295 AC: 644 AN: 2182

European-Non Finnish (NFE) AF: 0.202 AC: 50388 AN: 249954

Other (OTH) AF: 0.207 AC: 4953 AN: 23980

GnomAD4 genome AF: 0.195 AC: 29680 AN: 152090 Hom.: 3042 Cov.: 32 AF XY: 0.194 AC XY: 14456 AN XY: 74362

African (AFR) AF: 0.166 AC: 6880 AN: 41462

American (AMR) AF: 0.175 AC: 2676 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 380 AN: 3472

East Asian (EAS) AF: 0.339 AC: 1744 AN: 5152

South Asian (SAS) AF: 0.275 AC: 1324 AN: 4814

European-Finnish (FIN) AF: 0.185 AC: 1960 AN: 10608

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14046 AN: 67966

Other (OTH) AF: 0.209 AC: 442 AN: 2114

Alfa AF: 0.203 Hom.: 382

Bravo AF: 0.193

Asia WGS AF: 0.301 AC: 1048 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.77
PhyloP100		-0.28
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: rs28362508; hg19: chr12-111884415; COSMIC: COSV57986513; COSMIC: COSV57986513;