dbSNP rs1180787672: ATXN2:p.Gln16Gln (chr12-111598987-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001372574.1(ATXN2):c.48G>A(p.Gln16Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,465,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ATXN2
NM_001372574.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.00900

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 12-111598987-C-T is Benign according to our data. Variant chr12-111598987-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2643328.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.009 with no splicing effect.

BS2

High AC in GnomAd4 at 16 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.48G>A	p.Gln16Gln	synonymous	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
ATXN2	NM_002973.4		c.48G>A	p.Gln16Gln	synonymous	Exon 1 of 25	NP_002964.4	V9GY86
ATXN2	NM_001310121.1		c.-65+588G>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.48G>A	p.Gln16Gln	synonymous	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
ATXN2	ENST00000550104.5	TSL:1	c.528G>A	p.Gln176Gln	synonymous	Exon 1 of 25	ENSP00000446576.2	Q99700-1
ATXN2	ENST00000608853.5	TSL:1	c.48G>A	p.Gln16Gln	synonymous	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes

AF:

0.000114

AC:

AN:

140594

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000195

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000120

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000304

AC:

AN:

105302

AF XY:

0.000308

show subpopulations

Gnomad AFR exome

AF:

0.00448

Gnomad AMR exome

AF:

0.000531

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000158

Gnomad FIN exome

AF:

0.000127

Gnomad NFE exome

AF:

0.000130

Gnomad OTH exome

AF:

0.000315

GnomAD4 exome

AF:

0.000133

AC:

176

AN:

1324394

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

653588

show subpopulations

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

African (AFR)

AF:

0.0000856

AC:

AN:

23372

American (AMR)

AF:

0.000276

AC:

AN:

32646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24002

East Asian (EAS)

AF:

0.0000636

AC:

AN:

31448

South Asian (SAS)

AF:

0.000107

AC:

AN:

74736

European-Finnish (FIN)

AF:

0.0000269

AC:

AN:

37240

Middle Eastern (MID)

AF:

0.000489

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.000141

AC:

147

AN:

1041744

Other (OTH)

AF:

0.0000907

AC:

AN:

55112

⚠️ 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: 0.369

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:

0.000114

AC:

AN:

140664

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

69030

show subpopulations

African (AFR)

AF:

0.0000915

AC:

AN:

32786

American (AMR)

AF:

0.000136

AC:

AN:

14756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3414

East Asian (EAS)

AF:

0.000199

AC:

AN:

5022

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.000195

AC:

AN:

10276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000120

AC:

AN:

66454

Other (OTH)

AF:

0.00

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.00244

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.61

(source)

DANN

Benign

0.77

PhyloP100

-0.0090

PromoterAI

0.045

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