NM_001372574.1:c.51_56dupGCAGCA

Variant names:

• chr12-111598978-T-TTGCTGC
• rs193922927
• NM_001372574.1:c.51_56dupGCAGCA

Variant summary

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

The NM_001372574.1(ATXN2):​c.51_56dupGCAGCA​(p.Gln18_Gln19dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,292,820 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. Q19Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.273
• 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 12 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.51_56dupGCAGCA	p.Gln18_Gln19dup	disruptive_inframe_insertion	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.51_56dupGCAGCA	p.Gln18_Gln19dup	disruptive_inframe_insertion	Exon 1 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.-65+591_-65+596dupGCAGCA		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.51_56dupGCAGCA	p.Gln18_Gln19dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.531_536dupGCAGCA	p.Gln178_Gln179dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.51_56dupGCAGCA	p.Gln18_Gln19dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes AF: 0.0000872 AC: 12 AN: 137578 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: 0.000176

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 142 AN: 1155242 Hom.: 0 Cov.: 74 AF XY: 0.000136 AC XY: 77 AN XY: 568168

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

African (AFR) AF: 0.0000401 AC: 1 AN: 24914

American (AMR) AF: 0.00 AC: 0 AN: 27172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22082

East Asian (EAS) AF: 0.0000384 AC: 1 AN: 26040

South Asian (SAS) AF: 0.0000169 AC: 1 AN: 59218

European-Finnish (FIN) AF: 0.000125 AC: 4 AN: 32118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3382

European-Non Finnish (NFE) AF: 0.000140 AC: 128 AN: 912286

Other (OTH) AF: 0.000146 AC: 7 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: 0.0000872 AC: 12 AN: 137578 Hom.: 0 Cov.: 32 AF XY: 0.0000747 AC XY: 5 AN XY: 66910

African (AFR) AF: 0.00 AC: 0 AN: 37744

American (AMR) AF: 0.00 AC: 0 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: 0.000117 AC: 1 AN: 8574

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

European-Non Finnish (NFE) AF: 0.000176 AC: 11 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		0.27
Mutation Taster		=85/15	polymorphism

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;