12-111555908-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000673436.1(ATXN2):c.263G>A(p.Ser88Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,598,912 control chromosomes in the GnomAD database, including 9,139 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.069 ( 1288 hom., cov: 32)

Exomes 𝑓: 0.031 ( 7851 hom. )

Consequence

ATXN2
ENST00000673436.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

Publications

43 publications found

Variant links:

Genes affected

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)

ATXN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.5130534E-5).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000673436.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATXN2	NM_001372574.1	MANE Select	c.263G>A	p.Ser88Asn	missense	Exon 2 of 25	NP_001359503.1
ATXN2	NM_002973.4		c.263G>A	p.Ser88Asn	missense	Exon 2 of 25	NP_002964.4
ATXN2	NR_132311.2		n.544G>A		non_coding_transcript_exon	Exon 2 of 24

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATXN2	ENST00000673436.1	MANE Select	c.263G>A	p.Ser88Asn	missense	Exon 2 of 25	ENSP00000500925.1
ATXN2	ENST00000550104.5	TSL:1	c.743G>A	p.Ser248Asn	missense	Exon 2 of 25	ENSP00000446576.2
ATXN2	ENST00000608853.5	TSL:1	c.263G>A	p.Ser88Asn	missense	Exon 2 of 25	ENSP00000476504.1

Frequencies

GnomAD3 genomes

AF:

0.0686

AC:

10430

AN:

152046

Hom.:

1290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.0745

GnomAD2 exomes

AF:

0.0781

AC:

18758

AN:

240184

AF XY:

0.0701

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.166

Gnomad ASJ exome

AF:

0.00376

Gnomad EAS exome

AF:

0.563

Gnomad FIN exome

AF:

0.00353

Gnomad NFE exome

AF:

0.00336

Gnomad OTH exome

AF:

0.0473

GnomAD4 exome

AF:

0.0311

AC:

44945

AN:

1446746

Hom.:

7851

Cov.:

AF XY:

0.0315

AC XY:

22670

AN XY:

720046

show subpopulations

African (AFR)

AF:

0.116

AC:

3746

AN:

32338

American (AMR)

AF:

0.158

AC:

6663

AN:

42198

Ashkenazi Jewish (ASJ)

AF:

0.00366

AC:

AN:

25942

East Asian (EAS)

AF:

0.586

AC:

21844

AN:

37270

South Asian (SAS)

AF:

0.0787

AC:

6618

AN:

84142

European-Finnish (FIN)

AF:

0.00327

AC:

174

AN:

53234

Middle Eastern (MID)

AF:

0.0346

AC:

191

AN:

5516

European-Non Finnish (NFE)

AF:

0.00236

AC:

2609

AN:

1106396

Other (OTH)

AF:

0.0503

AC:

3005

AN:

59710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

1216

2432

3648

4864

6080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.0686

AC:

10443

AN:

152166

Hom.:

1288

Cov.:

AF XY:

0.0738

AC XY:

5494

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.117

AC:

4850

AN:

41486

American (AMR)

AF:

0.115

AC:

1757

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.566

AC:

2919

AN:

5154

South Asian (SAS)

AF:

0.102

AC:

493

AN:

4820

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00329

AC:

224

AN:

68012

Other (OTH)

AF:

0.0733

AC:

155

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

399

798

1198

1597

1996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0353

Hom.:

3646

Bravo

AF:

0.0837

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.120

AC:

528

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.0848

AC:

10293

Asia WGS

AF:

0.239

AC:

830

AN:

3478

EpiCase

AF:

0.00276

EpiControl

AF:

0.00495

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.70

MetaRNN

Benign

0.000075

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.44

REVEL

Benign

0.14

Sift

Benign

0.14

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.076

MPC

0.35

ClinPred

0.019

GERP RS

2.5

Varity_R

0.058

gMVP

0.44

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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