12-111598958-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001372574.1(ATXN2):c.77A>C(p.Gln26Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000878 in 1,480,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

ATXN2
NM_001372574.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

Publications

1 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 links:

ATXN2-AS (HGNC:51838): (ATXN2 antisense RNA)

ATXN2-AS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030268133).

BS2

High AC in GnomAd4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372574.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN2	NM_001372574.1	MANE Select	c.77A>C	p.Gln26Pro	missense	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
ATXN2	NM_002973.4		c.77A>C	p.Gln26Pro	missense	Exon 1 of 25	NP_002964.4	V9GY86
ATXN2	NM_001310121.1		c.-65+617A>C		intron	N/A	NP_001297050.1	Q2M2R5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN2	ENST00000673436.1	MANE Select	c.77A>C	p.Gln26Pro	missense	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
ATXN2	ENST00000550104.5	TSL:1	c.557A>C	p.Gln186Pro	missense	Exon 1 of 25	ENSP00000446576.2	Q99700-1
ATXN2	ENST00000608853.5	TSL:1	c.77A>C	p.Gln26Pro	missense	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes

AF:

0.000127

AC:

AN:

149234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000666

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00330

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000973

GnomAD2 exomes

AF:

0.000164

AC:

AN:

109996

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000470

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00225

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000834

AC:

111

AN:

1331580

Hom.:

Cov.:

AF XY:

0.0000761

AC XY:

AN XY:

657106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28198

American (AMR)

AF:

0.0000305

AC:

AN:

32790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24132

East Asian (EAS)

AF:

0.00292

AC:

AN:

31534

South Asian (SAS)

AF:

0.0000402

AC:

AN:

74632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00000670

AC:

AN:

1044248

Other (OTH)

AF:

0.000144

AC:

AN:

55444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000127

AC:

AN:

149342

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

73018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40372

American (AMR)

AF:

0.0000665

AC:

AN:

15034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00331

AC:

AN:

4830

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67288

Other (OTH)

AF:

0.000962

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000843

Hom.:

ExAC

AF:

0.000246

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.3

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.0056

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.36

M_CAP

Benign

0.051

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-1.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.31

REVEL

Benign

0.073

Sift

Benign

0.33

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.23

MVP

0.28

MPC

0.45

ClinPred

0.056

GERP RS

-1.9

PromoterAI

0.0044

Neutral

(source)

Varity_R

0.087

gMVP

0.57

Mutation Taster

=93/7

polymorphism

(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