chr12-111599125-G-A

Position:

• chr12-111599125-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000550104.5(ATXN2):​c.390C>T​(p.Arg130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,245,850 control chromosomes in the GnomAD database, including 351,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (31878 hom., cov: 29)
  • Exomes 𝑓: 0.75 (319773 hom.)
• Consequence: ATXN2 ENST00000550104.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.132

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-111599125-G-A is Benign according to our data. Variant chr12-111599125-G-A is described in ClinVar as [Benign]. Clinvar id is 128508.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-111599125-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.
• 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	Protein	UniProt
ATXN2	NM_001372574.1	c.-91C>T		5_prime_UTR_variant	1/25	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.-91C>T		5_prime_UTR_variant	1/25		NM_001372574.1	ENSP00000500925	A2

Frequencies

GnomAD3 genomes AF: 0.609 AC: 91398 AN: 150064 Hom.: 31888 Cov.: 29

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.0934

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.615

GnomAD3 exomes AF: 0.787 AC: 2080 AN: 2644 Hom.: 803 AF XY: 0.786 AC XY: 1469 AN XY: 1868

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.919

Gnomad SAS exome AF: 0.707

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.810

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.754 AC: 825798 AN: 1095676 Hom.: 319773 Cov.: 69 AF XY: 0.756 AC XY: 395318 AN XY: 522780

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.573

Gnomad4 ASJ exome AF: 0.874

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.671

Gnomad4 FIN exome AF: 0.815

Gnomad4 NFE exome AF: 0.785

Gnomad4 OTH exome AF: 0.696

GnomAD4 genome AF: 0.609 AC: 91402 AN: 150174 Hom.: 31878 Cov.: 29 AF XY: 0.609 AC XY: 44678 AN XY: 73366

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.579

Gnomad4 ASJ AF: 0.870

Gnomad4 EAS AF: 0.0939

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.823

Gnomad4 NFE AF: 0.785

Gnomad4 OTH AF: 0.618

Alfa AF: 0.685 Hom.: 4673

Bravo AF: 0.571

Asia WGS AF: 0.413 AC: 1382 AN: 3344

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

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

Oct 06, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.93

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

Other links and lift over

dbSNP: rs695872; hg19: chr12-112036929;