12-111598992-GC-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong 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
• Publications: 2 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-AS (HGNC:51838): (ATXN2 antisense RNA)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• 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 VariationId is 3055440.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 228 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372574.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.42delG	p.Gln14HisfsTer32	frameshift	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.42delG	p.Gln14HisfsTer32	frameshift	Exon 1 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.-65+582delG		intron	N/A	NP_001297050.1	Q2M2R5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.42delG	p.Gln14HisfsTer32	frameshift	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.522delG	p.Gln174HisfsTer32	frameshift	Exon 1 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.42delG	p.Gln14HisfsTer32	frameshift	Exon 1 of 25	ENSP00000476504.1	V9GY86

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

GnomAD2 exomes AF: 0.00214 AC: 206 AN: 96454 AF XY: 0.00220

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00252

Gnomad FIN exome AF: 0.00432

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00270

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00689 AC: 148 AN: 21474

American (AMR) AF: 0.00721 AC: 190 AN: 26368

Ashkenazi Jewish (ASJ) AF: 0.00465 AC: 80 AN: 17218

East Asian (EAS) AF: 0.00457 AC: 114 AN: 24962

South Asian (SAS) AF: 0.00606 AC: 347 AN: 57244

European-Finnish (FIN) AF: 0.00518 AC: 147 AN: 28398

Middle Eastern (MID) AF: 0.00558 AC: 19 AN: 3406

European-Non Finnish (NFE) AF: 0.00209 AC: 1785 AN: 855284

Other (OTH) AF: 0.00421 AC: 188 AN: 44618

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00467 AC: 154 AN: 32980

American (AMR) AF: 0.00156 AC: 23 AN: 14778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5042

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4786

European-Finnish (FIN) AF: 0.000975 AC: 10 AN: 10256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000433 AC: 29 AN: 66904

Other (OTH) AF: 0.00150 AC: 3 AN: 2002

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ATXN2-related disorder (1)
-	-	-	Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0050
Mutation Taster		=168/32	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: rs780952627; hg19: chr12-112036796; COSMIC: COSV108225762; COSMIC: COSV108225762;