Variant chr12-111555908-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001372574.1(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. 13/20 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
NM_001372574.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN2	NM_001372574.1 linkuse as main transcript	c.263G>A	p.Ser88Asn	missense_variant	2/25	ENST00000673436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN2	ENST00000673436.1 linkuse as main transcript	c.263G>A	p.Ser88Asn	missense_variant	2/25		NM_001372574.1	A2

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

GnomAD3 exomes

AF:

0.0781

AC:

18758

AN:

240184

Hom.:

3134

AF XY:

0.0701

AC XY:

9132

AN XY:

130236

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 SAS exome

AF:

0.0768

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

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.158

Gnomad4 ASJ exome

AF:

0.00366

Gnomad4 EAS exome

AF:

0.586

Gnomad4 SAS exome

AF:

0.0787

Gnomad4 FIN exome

AF:

0.00327

Gnomad4 NFE exome

AF:

0.00236

Gnomad4 OTH exome

AF:

0.0503

GnomAD4 genome

AF:

0.0686

AC:

10443

AN:

152166

Hom.:

1288

Cov.:

AF XY:

0.0738

AC XY:

5494

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.117

Gnomad4 AMR

AF:

0.115

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.566

Gnomad4 SAS

AF:

0.102

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00329

Gnomad4 OTH

AF:

0.0733

Alfa

AF:

0.0281

Hom.:

1647

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

T;T;.;T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.70

T;.;T;T;T;T

MetaRNN

Benign

0.000075

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

.;N;.;N;.;.

MutationTaster

Benign

0.050

P;P;P;P;P

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.44

.;N;.;N;.;.

REVEL

Benign

0.14

Sift

Benign

0.14

.;T;.;T;.;.

Sift4G

Benign

0.12

T;T;.;T;.;.

Polyphen

0.0

.;B;.;B;.;.

Vest4

0.076

MPC

0.35

ClinPred

0.019

GERP RS

2.5

Varity_R

0.058

gMVP

0.44

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over