12-111447547-ATGGGGTGGGGTGGGG-ATGGGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The ENST00000341259.7(SH2B3):c.1236+4_1236+13delTGGGGTGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 586,872 control chromosomes in the GnomAD database, including 28 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0034 ( 28 hom. )

Consequence

SH2B3
ENST00000341259.7 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.00

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ATXN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 12-111447547-ATGGGGTGGGG-A is Benign according to our data. Variant chr12-111447547-ATGGGGTGGGG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 4280834.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00156 (140/89558) while in subpopulation SAS AF = 0.00734 (20/2726). AF 95% confidence interval is 0.00486. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 28 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000341259.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.1236+19_1236+28delTGGGGTGGGG		intron	N/A	NP_005466.1	Q9UQQ2
	SH2B3	NM_001291424.1		c.630+19_630+28delTGGGGTGGGG		intron	N/A	NP_001278353.1	B7Z7K6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.1236+4_1236+13delTGGGGTGGGG	splice_region intron	N/A	ENSP00000345492.2	Q9UQQ2
SH2B3	ENST00000896496.1		c.1239+4_1239+13delTGGGGTGGGG	splice_region intron	N/A	ENSP00000566555.1
SH2B3	ENST00000935782.1		c.1239+4_1239+13delTGGGGTGGGG	splice_region intron	N/A	ENSP00000605841.1

Frequencies

GnomAD3 genomes

AF:

0.00157

AC:

140

AN:

89434

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00277

Gnomad ASJ

AF:

0.000622

Gnomad EAS

AF:

0.000468

Gnomad SAS

AF:

0.00734

Gnomad FIN

AF:

0.00709

Gnomad MID

AF:

0.00500

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.000825

GnomAD2 exomes

AF:

0.00200

AC:

369

AN:

184788

AF XY:

0.00215

show subpopulations

Gnomad AFR exome

AF:

0.000874

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.00364

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.00153

GnomAD4 exome

AF:

0.00344

AC:

1710

AN:

497314

Hom.:

AF XY:

0.00361

AC XY:

942

AN XY:

260642

show subpopulations

African (AFR)

AF:

0.00139

AC:

AN:

19468

American (AMR)

AF:

0.00169

AC:

AN:

26030

Ashkenazi Jewish (ASJ)

AF:

0.000552

AC:

AN:

9064

East Asian (EAS)

AF:

0.000283

AC:

AN:

35358

South Asian (SAS)

AF:

0.00639

AC:

340

AN:

53230

European-Finnish (FIN)

AF:

0.00513

AC:

146

AN:

28448

Middle Eastern (MID)

AF:

0.00205

AC:

AN:

3418

European-Non Finnish (NFE)

AF:

0.00360

AC:

1075

AN:

298620

Other (OTH)

AF:

0.00237

AC:

AN:

23678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.667

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00156

AC:

140

AN:

89558

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

AN XY:

42488

show subpopulations

African (AFR)

AF:

0.000258

AC:

AN:

31004

American (AMR)

AF:

0.00276

AC:

AN:

8322

Ashkenazi Jewish (ASJ)

AF:

0.000622

AC:

AN:

1608

East Asian (EAS)

AF:

0.000469

AC:

AN:

4266

South Asian (SAS)

AF:

0.00734

AC:

AN:

2726

European-Finnish (FIN)

AF:

0.00709

AC:

AN:

3384

Middle Eastern (MID)

AF:

0.00543

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.00165

AC:

AN:

36430

Other (OTH)

AF:

0.000816

AC:

AN:

1226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.611

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000929

Hom.:

272

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over