12-111598993-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 128509.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-111598993-C-T is described in Lovd as [Benign]. Variant chr12-111598993-C-T is described in Lovd as [Likely_benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1 link	c.42G>A	p.Gln14Gln	synonymous_variant	Exon 1 of 25	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1 link	c.42G>A	p.Gln14Gln	synonymous_variant	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1		A0A5F9ZI57

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

GnomAD3 exomes

AF:

0.693

AC:

71463

AN:

103176

Hom.:

23376

AF XY:

0.690

AC XY:

39339

AN XY:

57044

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 SAS exome

AF:

0.646

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

Gnomad4 AFR exome

AF:

0.679

Gnomad4 AMR exome

AF:

0.627

Gnomad4 ASJ exome

AF:

0.769

Gnomad4 EAS exome

AF:

0.652

Gnomad4 SAS exome

AF:

0.632

Gnomad4 FIN exome

AF:

0.728

Gnomad4 NFE exome

AF:

0.719

Gnomad4 OTH exome

AF:

0.694

GnomAD4 genome

AF:

0.754

AC:

112695

AN:

149428

Hom.:

42405

Cov.:

AF XY:

0.756

AC XY:

55188

AN XY:

72986

show subpopulations

Gnomad4 AFR

AF:

0.708

Gnomad4 AMR

AF:

0.722

Gnomad4 ASJ

AF:

0.870

Gnomad4 EAS

AF:

0.658

Gnomad4 SAS

AF:

0.729

Gnomad4 FIN

AF:

0.818

Gnomad4 NFE

AF:

0.782

Gnomad4 OTH

AF:

0.745

Alfa

AF:

0.732

Hom.:

2804

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 2

Benign:1

Feb 07, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.4

DANN

Benign

0.84

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