12-111447547-A-ATGGGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000341259.7(SH2B3):c.1236+3_1236+4insTGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0024 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

SH2B3
ENST00000341259.7 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.80

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 -16 ACMG points.

BP6

Variant 12-111447547-A-ATGGGG is Benign according to our data. Variant chr12-111447547-A-ATGGGG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1285139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00239 (1189/498274) while in subpopulation NFE AF = 0.00345 (1033/299050). AF 95% confidence interval is 0.00328. There are 4 homozygotes in GnomAdExome4. There are 621 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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+24_1236+28dupTGGGG		intron	N/A	NP_005466.1	Q9UQQ2
	SH2B3	NM_001291424.1		c.630+24_630+28dupTGGGG		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+3_1236+4insTGGGG	splice_region intron	N/A	ENSP00000345492.2	Q9UQQ2
SH2B3	ENST00000896496.1		c.1239+3_1239+4insTGGGG	splice_region intron	N/A	ENSP00000566555.1
SH2B3	ENST00000935782.1		c.1239+3_1239+4insTGGGG	splice_region intron	N/A	ENSP00000605841.1

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

181

AN:

89444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000453

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000482

Gnomad ASJ

AF:

0.00871

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00184

Gnomad FIN

AF:

0.000887

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00384

Gnomad OTH

AF:

0.000825

GnomAD2 exomes

AF:

0.000617

AC:

114

AN:

184788

AF XY:

0.000598

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.000394

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.0000624

Gnomad FIN exome

AF:

0.000121

Gnomad NFE exome

AF:

0.000962

Gnomad OTH exome

AF:

0.000254

GnomAD4 exome

AF:

0.00239

AC:

1189

AN:

498274

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

621

AN XY:

261136

show subpopulations

African (AFR)

AF:

0.000205

AC:

AN:

19554

American (AMR)

AF:

0.000344

AC:

AN:

26138

Ashkenazi Jewish (ASJ)

AF:

0.00869

AC:

AN:

9092

East Asian (EAS)

AF:

0.0000282

AC:

AN:

35510

South Asian (SAS)

AF:

0.000206

AC:

AN:

53316

European-Finnish (FIN)

AF:

0.000246

AC:

AN:

28470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3422

European-Non Finnish (NFE)

AF:

0.00345

AC:

1033

AN:

299050

Other (OTH)

AF:

0.00190

AC:

AN:

23722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00202

AC:

181

AN:

89568

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

AN XY:

42494

show subpopulations

African (AFR)

AF:

0.000451

AC:

AN:

31010

American (AMR)

AF:

0.000481

AC:

AN:

8322

Ashkenazi Jewish (ASJ)

AF:

0.00871

AC:

AN:

1608

East Asian (EAS)

AF:

0.00

AC:

AN:

4266

South Asian (SAS)

AF:

0.00183

AC:

AN:

2726

European-Finnish (FIN)

AF:

0.000887

AC:

AN:

3384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.00384

AC:

140

AN:

36434

Other (OTH)

AF:

0.000816

AC:

AN:

1226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000406

Hom.:

272

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.8

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