dbSNP rs76696028: ATXN2:p.Gln19Gln (chr12-111598978-T-C) – 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.57A>G(p.Gln19Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0441 in 1,222,094 control chromosomes in the GnomAD database, including 2,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.13 ( 1688 hom., cov: 30)

Exomes 𝑓: 0.033 ( 1110 hom. )

Consequence

ATXN2
NM_001372574.1 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: -2.34

Publications

9 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

BP6

Variant 12-111598978-T-C is Benign according to our data. Variant chr12-111598978-T-C is described in ClinVar as Benign. ClinVar VariationId is 522370.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 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.57A>G	p.Gln19Gln	synonymous	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
ATXN2	NM_002973.4		c.57A>G	p.Gln19Gln	synonymous	Exon 1 of 25	NP_002964.4	V9GY86
ATXN2	NM_001310121.1		c.-65+597A>G		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.57A>G	p.Gln19Gln	synonymous	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
ATXN2	ENST00000550104.5	TSL:1	c.537A>G	p.Gln179Gln	synonymous	Exon 1 of 25	ENSP00000446576.2	Q99700-1
ATXN2	ENST00000608853.5	TSL:1	c.57A>G	p.Gln19Gln	synonymous	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

17828

AN:

136802

Hom.:

1683

Cov.:

show subpopulations

Gnomad AFR

AF:

0.344

Gnomad AMI

AF:

0.0772

Gnomad AMR

AF:

0.0781

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.0290

Gnomad SAS

AF:

0.0442

Gnomad FIN

AF:

0.0332

Gnomad MID

AF:

0.0461

Gnomad NFE

AF:

0.0473

Gnomad OTH

AF:

0.102

GnomAD4 exome

AF:

0.0332

AC:

36052

AN:

1085220

Hom.:

1110

Cov.:

AF XY:

0.0331

AC XY:

17736

AN XY:

535156

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.334

AC:

7450

AN:

22322

American (AMR)

AF:

0.0537

AC:

1392

AN:

25932

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

347

AN:

21688

East Asian (EAS)

AF:

0.0202

AC:

524

AN:

25910

South Asian (SAS)

AF:

0.0439

AC:

2515

AN:

57314

European-Finnish (FIN)

AF:

0.0306

AC:

968

AN:

31630

Middle Eastern (MID)

AF:

0.0564

AC:

183

AN:

3244

European-Non Finnish (NFE)

AF:

0.0240

AC:

20435

AN:

851446

Other (OTH)

AF:

0.0489

AC:

2238

AN:

45734

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.368

Heterozygous variant carriers

1605

3211

4816

6422

8027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.131

AC:

17872

AN:

136874

Hom.:

1688

Cov.:

AF XY:

0.126

AC XY:

8400

AN XY:

66630

show subpopulations

African (AFR)

AF:

0.344

AC:

12895

AN:

37490

American (AMR)

AF:

0.0781

AC:

1083

AN:

13864

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

AN:

3208

East Asian (EAS)

AF:

0.0287

AC:

124

AN:

4324

South Asian (SAS)

AF:

0.0442

AC:

190

AN:

4302

European-Finnish (FIN)

AF:

0.0332

AC:

283

AN:

8532

Middle Eastern (MID)

AF:

0.0500

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.0473

AC:

2943

AN:

62176

Other (OTH)

AF:

0.102

AC:

192

AN:

1876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

514

1029

1543

2058

2572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.115

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Spinocerebellar ataxia type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.3

(source)

DANN

Benign

0.11

PhyloP100

-2.3

PromoterAI

-0.053

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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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