12-111598978-TTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr12-111598978-TTGC-T
• rs193922927
• NM_001372574.1:c.54_56delGCA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001372574.1(ATXN2):​c.54_56delGCA​(p.Gln19del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,288,308 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q18Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• 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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001372574.1
• BS2: High AC in GnomAd4 at 6 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.54_56delGCA	p.Gln19del	disruptive_inframe_deletion	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.54_56delGCA	p.Gln19del	disruptive_inframe_deletion	Exon 1 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.-65+594_-65+596delGCA		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.54_56delGCA	p.Gln19del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.534_536delGCA	p.Gln179del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.54_56delGCA	p.Gln19del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes AF: 0.0000436 AC: 6 AN: 137574 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000801

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000218 AC: 251 AN: 1150662 Hom.: 0 AF XY: 0.000216 AC XY: 122 AN XY: 565966

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

African (AFR) AF: 0.0000402 AC: 1 AN: 24888

American (AMR) AF: 0.000777 AC: 21 AN: 27010

Ashkenazi Jewish (ASJ) AF: 0.000136 AC: 3 AN: 22036

East Asian (EAS) AF: 0.0000384 AC: 1 AN: 26028

South Asian (SAS) AF: 0.0000169 AC: 1 AN: 59024

European-Finnish (FIN) AF: 0.000593 AC: 19 AN: 32064

Middle Eastern (MID) AF: 0.000297 AC: 1 AN: 3372

European-Non Finnish (NFE) AF: 0.000205 AC: 186 AN: 908434

Other (OTH) AF: 0.000377 AC: 18 AN: 47806

⚠️ 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: 0.0000436 AC: 6 AN: 137646 Hom.: 0 Cov.: 32 AF XY: 0.0000597 AC XY: 4 AN XY: 67000

African (AFR) AF: 0.00 AC: 0 AN: 37840

American (AMR) AF: 0.00 AC: 0 AN: 13918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3214

East Asian (EAS) AF: 0.00 AC: 0 AN: 4340

South Asian (SAS) AF: 0.00 AC: 0 AN: 4322

European-Finnish (FIN) AF: 0.000117 AC: 1 AN: 8574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.0000801 AC: 5 AN: 62444

Other (OTH) AF: 0.00 AC: 0 AN: 1884

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=88/12	polymorphism

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: rs193922927; hg19: chr12-112036782; COSMIC: COSV66483328; COSMIC: COSV66483328;