12-111599196-G-C

Position:

chr12-111599196-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000550104.5(ATXN2):c.319C>G(p.Leu107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,209,904 control chromosomes in the GnomAD database, including 341,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.61 ( 31645 hom., cov: 29)

Exomes 𝑓: 0.75 ( 309828 hom. )

Consequence

ATXN2
ENST00000550104.5 missense

Scores

Clinical Significance

Benign/Likely benign no assertion criteria provided B:3

Conservation

PhyloP100: -0.0670

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.9935905E-7).

BP6

Variant 12-111599196-G-C is Benign according to our data. Variant chr12-111599196-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 128507.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-111599196-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN2	NM_001372574.1 linkuse as main transcript	c.-162C>G		5_prime_UTR_variant	1/25	ENST00000673436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN2	ENST00000673436.1 linkuse as main transcript	c.-162C>G		5_prime_UTR_variant	1/25		NM_001372574.1	A2

Frequencies

GnomAD3 genomes

AF:

0.607

AC:

90782

AN:

149450

Hom.:

31655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.309

Gnomad AMI

AF:

0.854

Gnomad AMR

AF:

0.579

Gnomad ASJ

AF:

0.871

Gnomad EAS

AF:

0.0926

Gnomad SAS

AF:

0.631

Gnomad FIN

AF:

0.824

Gnomad MID

AF:

0.610

Gnomad NFE

AF:

0.785

Gnomad OTH

AF:

0.615

GnomAD3 exomes

AF:

0.773

AC:

167

AN:

216

Hom.:

AF XY:

0.754

AC XY:

101

AN XY:

134

show subpopulations

Gnomad AMR exome

AF:

0.00

Gnomad SAS exome

AF:

0.500

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.779

Gnomad OTH exome

AF:

1.00

GnomAD4 exome

AF:

0.754

AC:

799904

AN:

1060356

Hom.:

309828

Cov.:

AF XY:

0.757

AC XY:

379834

AN XY:

501958

show subpopulations

Gnomad4 AFR exome

AF:

0.296

Gnomad4 AMR exome

AF:

0.575

Gnomad4 ASJ exome

AF:

0.874

Gnomad4 EAS exome

AF:

0.140

Gnomad4 SAS exome

AF:

0.649

Gnomad4 FIN exome

AF:

0.814

Gnomad4 NFE exome

AF:

0.785

Gnomad4 OTH exome

AF:

0.696

GnomAD4 genome

AF:

0.607

AC:

90784

AN:

149548

Hom.:

31645

Cov.:

AF XY:

0.607

AC XY:

44304

AN XY:

72962

show subpopulations

Gnomad4 AFR

AF:

0.309

Gnomad4 AMR

AF:

0.578

Gnomad4 ASJ

AF:

0.871

Gnomad4 EAS

AF:

0.0931

Gnomad4 SAS

AF:

0.631

Gnomad4 FIN

AF:

0.824

Gnomad4 NFE

AF:

0.785

Gnomad4 OTH

AF:

0.618

Alfa

AF:

0.685

Hom.:

4765

Bravo

AF:

0.572

ExAC

AF:

0.389

AC:

6426

Asia WGS

AF:

0.421

AC:

1302

AN:

3094

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Spinocerebellar ataxia type 2

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Feb 07, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.071

T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.44

.;T

MetaRNN

Benign

6.0e-7

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.050

N;N

REVEL

Benign

0.11

Sift

Benign

0.32

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0

B;B

Vest4

0.037

MPC

0.37

ClinPred

0.040

GERP RS

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.056

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over