Variant chr12-111446611-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.277

Variant links:

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]

SH2B3 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SH2B3	NM_005475.3 link	c.733-142T>C		intron_variant		ENST00000341259.7	NP_005466.1	Q9UQQ2Q59H48

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SH2B3	ENST00000341259.7 link	c.733-142T>C	intron_variant	1	NM_005475.3	ENSP00000345492.2	Q9UQQ2
SH2B3	ENST00000538307.1 link	c.127-142T>C	intron_variant	2		ENSP00000440597.1	F5GYM4
ATXN2	ENST00000642389.2 link	n.*171-2424A>G	intron_variant			ENSP00000496055.2	A0A2R8Y7E6

Frequencies

GnomAD3 genomes

AF:

0.195

AC:

29673

AN:

151972

Hom.:

3041

Cov.:

show subpopulations

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

show subpopulations

Gnomad4 AFR exome

AF:

0.160

Gnomad4 AMR exome

AF:

0.158

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.280

Gnomad4 SAS exome

AF:

0.273

Gnomad4 FIN exome

AF:

0.187

Gnomad4 NFE exome

AF:

0.202

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.195

AC:

29680

AN:

152090

Hom.:

3042

Cov.:

AF XY:

0.194

AC XY:

14456

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.166

Gnomad4 AMR

AF:

0.175

Gnomad4 ASJ

AF:

0.109

Gnomad4 EAS

AF:

0.339

Gnomad4 SAS

AF:

0.275

Gnomad4 FIN

AF:

0.185

Gnomad4 NFE

AF:

0.207

Gnomad4 OTH

AF:

0.209

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

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.3

DANN

Benign

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over