12-111598992-GC-G

Variant names:

• chr12-111598992-GC-G
• rs780952627
• NM_001372574.1:c.42delG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001372574.1(ATXN2):​c.42delG​(p.Gln14HisfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,220,360 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. Q14Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (6 hom.)
• Consequence: ATXN2 NM_001372574.1 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 0.00500

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 12-111598992-GC-G is Benign according to our data. Variant chr12-111598992-GC-G is described in ClinVar as [Likely_benign]. Clinvar id is 3055440.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.42delG	p.Gln14HisfsTer32	frameshift_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	c.42delG	p.Gln14HisfsTer32	frameshift_variant	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 227 AN: 141320 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.000975

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000433

Gnomad OTH AF: 0.00152

GnomAD4 exome AF: 0.00280 AC: 3018 AN: 1078972 Hom.: 6 Cov.: 71 AF XY: 0.00284 AC XY: 1502 AN XY: 529110

Gnomad4 AFR exome AF: 0.00689

Gnomad4 AMR exome AF: 0.00721

Gnomad4 ASJ exome AF: 0.00465

Gnomad4 EAS exome AF: 0.00457

Gnomad4 SAS exome AF: 0.00606

Gnomad4 FIN exome AF: 0.00518

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00161 AC: 228 AN: 141388 Hom.: 2 Cov.: 31 AF XY: 0.00156 AC XY: 108 AN XY: 69328

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.00156

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.000975

Gnomad4 NFE AF: 0.000433

Gnomad4 OTH AF: 0.00150

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

ATXN2-related disorder Benign:1

Jun 05, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Parkinson disease, late-onset Other:1

-

GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 02-14-2020 by Macrogen. GenomeConnect-Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

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: rs780952627; hg19: chr12-112036796;