12-111447568-T-G

Variant names:

• chr12-111447568-T-G
• rs1171636888
• NM_005475.3:c.1236+24T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_005475.3(SH2B3):​c.1236+24T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (0 hom., cov: 0)
  • Exomes 𝑓: 0.035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2B3 NM_005475.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-111447568-T-G is Benign according to our data. Variant chr12-111447568-T-G is described in ClinVar as [Benign]. Clinvar id is 1278036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.1236+24T>G		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+24T>G		intron_variant	Intron 6 of 7	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000538307.1	c.630+24T>G		intron_variant	Intron 5 of 6	2		ENSP00000440597.1
ATXN2	ENST00000642389.2	n.*171-3381A>C		intron_variant	Intron 26 of 26			ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 305 AN: 32982 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00755

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00472

Gnomad MID AF: 0.0119

Gnomad NFE AF: 0.00460

Gnomad OTH AF: 0.00905

GnomAD3 exomes AF: 0.0175 AC: 2274 AN: 129672 Hom.: 0 AF XY: 0.0162 AC XY: 1186 AN XY: 73410

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.0360

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.0956

Gnomad SAS exome AF: 0.0210

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.0263

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0350 AC: 7784 AN: 222600 Hom.: 0 Cov.: 0 AF XY: 0.0360 AC XY: 4324 AN XY: 120050

Gnomad4 AFR exome AF: 0.0732

Gnomad4 AMR exome AF: 0.0665

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.0850

Gnomad4 SAS exome AF: 0.0711

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0402

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00924 AC: 305 AN: 33014 Hom.: 0 Cov.: 0 AF XY: 0.0100 AC XY: 155 AN XY: 15502

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.00753

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0323

Gnomad4 SAS AF: 0.0165

Gnomad4 FIN AF: 0.00472

Gnomad4 NFE AF: 0.00460

Gnomad4 OTH AF: 0.00885

Alfa AF: 0.00141 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.1
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs1171636888; hg19: chr12-111885372; COSMIC: COSV57982993; COSMIC: COSV57982993;