12-111598974-GC-G

Variant names:

• chr12-111598974-GC-G
• rs757862555
• NM_001372574.1:c.60delG

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.60delG​(p.Gln20HisfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,457,444 control chromosomes in the GnomAD database, including 41 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0077 (5 hom., cov: 30)
  • Exomes 𝑓: 0.0065 (36 hom.)
• Consequence: ATXN2 NM_001372574.1 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.274
• 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. Fraction of 0.983 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 12-111598974-GC-G is Benign according to our data. Variant chr12-111598974-GC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3045503.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 1139 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.60delG	p.Gln20HisfsTer26	frameshift	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.60delG	p.Gln20HisfsTer26	frameshift	Exon 1 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.-65+600delG		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.60delG	p.Gln20HisfsTer26	frameshift	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.540delG	p.Gln180HisfsTer26	frameshift	Exon 1 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.60delG	p.Gln20HisfsTer26	frameshift	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1136 AN: 148526 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.00756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00399

Gnomad FIN AF: 0.00296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00851

Gnomad OTH AF: 0.0112

GnomAD2 exomes AF: 0.00254 AC: 284 AN: 111948 AF XY: 0.00282

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00430

Gnomad EAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00145

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00648 AC: 8486 AN: 1308836 Hom.: 36 Cov.: 68 AF XY: 0.00652 AC XY: 4206 AN XY: 644922

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

African (AFR) AF: 0.00665 AC: 172 AN: 25860

American (AMR) AF: 0.00571 AC: 178 AN: 31176

Ashkenazi Jewish (ASJ) AF: 0.00803 AC: 191 AN: 23780

East Asian (EAS) AF: 0.0165 AC: 494 AN: 29986

South Asian (SAS) AF: 0.00632 AC: 441 AN: 69728

European-Finnish (FIN) AF: 0.00480 AC: 175 AN: 36464

Middle Eastern (MID) AF: 0.00953 AC: 37 AN: 3884

European-Non Finnish (NFE) AF: 0.00622 AC: 6434 AN: 1033766

Other (OTH) AF: 0.00672 AC: 364 AN: 54192

⚠️ 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: 0.00766 AC: 1139 AN: 148608 Hom.: 5 Cov.: 30 AF XY: 0.00706 AC XY: 513 AN XY: 72648

African (AFR) AF: 0.00764 AC: 304 AN: 39794

American (AMR) AF: 0.00607 AC: 91 AN: 14992

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3466

East Asian (EAS) AF: 0.0104 AC: 52 AN: 4990

South Asian (SAS) AF: 0.00400 AC: 19 AN: 4750

European-Finnish (FIN) AF: 0.00296 AC: 30 AN: 10138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00850 AC: 571 AN: 67208

Other (OTH) AF: 0.0111 AC: 23 AN: 2070

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ATXN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.27
Mutation Taster		=185/15	disease causing (fs/PTC)

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: rs757862555; hg19: chr12-112036778;