chr12-111598978-TTGCTGC-T

Variant names:

• chr12-111598978-TTGCTGC-T
• rs193922927
• NM_001372574.1:c.51_56delGCAGCA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001372574.1(ATXN2):​c.51_56delGCAGCA​(p.Gln18_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 0.0000291 in 137,578 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001372574.1

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.51_56delGCAGCA	p.Gln18_Gln19del	disruptive_inframe_deletion	Exon 1 of 25	NP_001359503.1
	ATXN2	NM_002973.4		c.51_56delGCAGCA	p.Gln18_Gln19del	disruptive_inframe_deletion	Exon 1 of 25	NP_002964.4
	ATXN2	NR_132311.2		n.332_337delGCAGCA		non_coding_transcript_exon	Exon 1 of 24

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.51_56delGCAGCA	p.Gln18_Gln19del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000500925.1
	ATXN2	ENST00000550104.5	TSL:1	c.531_536delGCAGCA	p.Gln178_Gln179del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000446576.2
	ATXN2	ENST00000608853.5	TSL:1	c.51_56delGCAGCA	p.Gln18_Gln19del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000476504.1

Frequencies

GnomAD3 genomes AF: 0.0000291 AC: 4 AN: 137578 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000160

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000571 AC: 66 AN: 1155216 Hom.: 0 AF XY: 0.0000546 AC XY: 31 AN XY: 568138

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

African (AFR) AF: 0.00 AC: 0 AN: 24914

American (AMR) AF: 0.000184 AC: 5 AN: 27168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22080

East Asian (EAS) AF: 0.00 AC: 0 AN: 26040

South Asian (SAS) AF: 0.000220 AC: 13 AN: 59216

European-Finnish (FIN) AF: 0.0000311 AC: 1 AN: 32118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3380

European-Non Finnish (NFE) AF: 0.0000482 AC: 44 AN: 912270

Other (OTH) AF: 0.0000625 AC: 3 AN: 48030

⚠️ 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: 0.0000291 AC: 4 AN: 137578 Hom.: 0 Cov.: 32 AF XY: 0.0000149 AC XY: 1 AN XY: 66910

African (AFR) AF: 0.0000530 AC: 2 AN: 37744

American (AMR) AF: 0.0000719 AC: 1 AN: 13900

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4356

South Asian (SAS) AF: 0.00 AC: 0 AN: 4338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000160 AC: 1 AN: 62456

Other (OTH) AF: 0.00 AC: 0 AN: 1864

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=179/21	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922927; hg19: chr12-112036782;