12-111598868-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001372574.1(ATXN2):c.167C>T(p.Ser56Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000201 in 1,492,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S56W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

ATXN2
NM_001372574.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0210

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10447943).

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.167C>T	p.Ser56Leu	missense	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
ATXN2	NM_002973.4		c.167C>T	p.Ser56Leu	missense	Exon 1 of 25	NP_002964.4	V9GY86
ATXN2	NM_001310121.1		c.-65+707C>T		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.167C>T	p.Ser56Leu	missense	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
ATXN2	ENST00000550104.5	TSL:1	c.647C>T	p.Ser216Leu	missense	Exon 1 of 25	ENSP00000446576.2	Q99700-1
ATXN2	ENST00000608853.5	TSL:1	c.167C>T	p.Ser56Leu	missense	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151370

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000105

AC:

AN:

94872

AF XY:

0.0000188

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000145

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000149

AC:

AN:

1340924

Hom.:

Cov.:

AF XY:

0.00000302

AC XY:

AN XY:

661360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27424

American (AMR)

AF:

0.00

AC:

AN:

31446

Ashkenazi Jewish (ASJ)

AF:

0.0000843

AC:

AN:

23720

East Asian (EAS)

AF:

0.00

AC:

AN:

30316

South Asian (SAS)

AF:

0.00

AC:

AN:

75444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3952

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1059678

Other (OTH)

AF:

0.00

AC:

AN:

55774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00000661

AC:

AN:

151370

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41356

American (AMR)

AF:

0.0000658

AC:

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67722

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0082

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.021

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.30

REVEL

Benign

0.046

Sift

Uncertain

0.021

Sift4G

Uncertain

0.029

Polyphen

0.14

Vest4

0.083

MutPred

0.24

Loss of phosphorylation at S216 (P = 9e-04)

MVP

0.25

MPC

0.33

ClinPred

0.088

GERP RS

2.4

PromoterAI

0.041

Neutral

(source)

Varity_R

0.10

gMVP

0.44

Mutation Taster

=95/5

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over