12-111494996-C-T

Variant names:

• chr12-111494996-C-T
• rs7137828
• NM_001372574.1:c.1936-6216G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372574.1(ATXN2):​c.1936-6216G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 151,974 control chromosomes in the GnomAD database, including 37,613 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (37613 hom., cov: 30)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 84 publications found

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 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.1936-6216G>A		intron_variant	Intron 14 of 24	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.1936-6216G>A		intron_variant	Intron 14 of 24		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102497 AN: 151856 Hom.: 37538 Cov.: 30

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.646

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.675 AC: 102636 AN: 151974 Hom.: 37613 Cov.: 30 AF XY: 0.687 AC XY: 51027 AN XY: 74262

African (AFR) AF: 0.918 AC: 38099 AN: 41506

American (AMR) AF: 0.707 AC: 10778 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1143 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5160 AN: 5170

South Asian (SAS) AF: 0.906 AC: 4364 AN: 4816

European-Finnish (FIN) AF: 0.594 AC: 6244 AN: 10504

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.512 AC: 34800 AN: 67942

Other (OTH) AF: 0.649 AC: 1370 AN: 2110

Alfa AF: 0.603 Hom.: 15530

Bravo AF: 0.690

Asia WGS AF: 0.943 AC: 3278 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.66
DANN	Benign	0.17
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7137828; hg19: chr12-111932800;