Genetic Variant ATXN2:p.Gln14Gln (chr12-111598993-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001372574.1(ATXN2):c.42G>A(p.Gln14Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 149,428 control chromosomes in the GnomAD database, including 42,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.75 ( 42405 hom., cov: 31)

Exomes 𝑓: 0.71 ( 311244 hom. )

Failed GnomAD Quality Control

Consequence

ATXN2
NM_001372574.1 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:4

Conservation

PhyloP100: 0.00500

Publications

19 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 12-111598993-C-T is Benign according to our data. Variant chr12-111598993-C-T is described in ClinVar as Benign. ClinVar VariationId is 128509.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.005 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

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.42G>A	p.Gln14Gln	synonymous	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
ATXN2	NM_002973.4		c.42G>A	p.Gln14Gln	synonymous	Exon 1 of 25	NP_002964.4	V9GY86
ATXN2	NM_001310121.1		c.-65+582G>A		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.42G>A	p.Gln14Gln	synonymous	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
ATXN2	ENST00000550104.5	TSL:1	c.522G>A	p.Gln174Gln	synonymous	Exon 1 of 25	ENSP00000446576.2	Q99700-1
ATXN2	ENST00000608853.5	TSL:1	c.42G>A	p.Gln14Gln	synonymous	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes

AF:

0.754

AC:

112631

AN:

149326

Hom.:

42385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.708

Gnomad AMI

AF:

0.844

Gnomad AMR

AF:

0.722

Gnomad ASJ

AF:

0.870

Gnomad EAS

AF:

0.658

Gnomad SAS

AF:

0.729

Gnomad FIN

AF:

0.818

Gnomad MID

AF:

0.679

Gnomad NFE

AF:

0.782

Gnomad OTH

AF:

0.742

GnomAD2 exomes

AF:

0.693

AC:

71463

AN:

103176

AF XY:

0.690

show subpopulations

Gnomad AFR exome

AF:

0.694

Gnomad AMR exome

AF:

0.643

Gnomad ASJ exome

AF:

0.768

Gnomad EAS exome

AF:

0.654

Gnomad FIN exome

AF:

0.770

Gnomad NFE exome

AF:

0.718

Gnomad OTH exome

AF:

0.699

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.709

AC:

940173

AN:

1325742

Hom.:

311244

Cov.:

AF XY:

0.707

AC XY:

462584

AN XY:

654028

show subpopulations

African (AFR)

AF:

0.679

AC:

18200

AN:

26794

American (AMR)

AF:

0.627

AC:

20046

AN:

31960

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

18120

AN:

23558

East Asian (EAS)

AF:

0.652

AC:

20233

AN:

31030

South Asian (SAS)

AF:

0.632

AC:

46919

AN:

74196

European-Finnish (FIN)

AF:

0.728

AC:

26931

AN:

36984

Middle Eastern (MID)

AF:

0.638

AC:

2590

AN:

4062

European-Non Finnish (NFE)

AF:

0.719

AC:

748972

AN:

1042148

Other (OTH)

AF:

0.694

AC:

38162

AN:

55010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

10433

20865

31298

41730

52163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19696

39392

59088

78784

98480

<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:

0.754

AC:

112695

AN:

149428

Hom.:

42405

Cov.:

AF XY:

0.756

AC XY:

55188

AN XY:

72986

show subpopulations

African (AFR)

AF:

0.708

AC:

28392

AN:

40094

American (AMR)

AF:

0.722

AC:

10917

AN:

15118

Ashkenazi Jewish (ASJ)

AF:

0.870

AC:

3008

AN:

3458

East Asian (EAS)

AF:

0.658

AC:

3308

AN:

5030

South Asian (SAS)

AF:

0.729

AC:

3498

AN:

4800

European-Finnish (FIN)

AF:

0.818

AC:

8386

AN:

10256

Middle Eastern (MID)

AF:

0.690

AC:

200

AN:

290

European-Non Finnish (NFE)

AF:

0.782

AC:

52696

AN:

67424

Other (OTH)

AF:

0.745

AC:

1549

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1389

2777

4166

5554

6943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.732

Hom.:

2804

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Spinocerebellar ataxia type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.4

(source)

DANN

Benign

0.84

PhyloP100

0.0050

PromoterAI

0.052

Neutral

(source)

Mutation Taster

=100/0

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