rs746198949

Variant names:

• chr12-111598966-CTGCTGCTGCTGT-C
• rs746198949
• NM_001372574.1:c.57_68delACAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001372574.1(ATXN2):​c.57_68delACAGCAGCAGCA​(p.Gln20_Gln23del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,502,910 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. Q19Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.624
• Publications: 0 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001372574.1
• BP6: Variant 12-111598966-CTGCTGCTGCTGT-C is Benign according to our data. Variant chr12-111598966-CTGCTGCTGCTGT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2643324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 89 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.57_68delACAGCAGCAGCA	p.Gln20_Gln23del	disruptive_inframe_deletion	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.57_68delACAGCAGCAGCA	p.Gln20_Gln23del	disruptive_inframe_deletion	Exon 1 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.-65+597_-65+608delACAGCAGCAGCA		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.57_68delACAGCAGCAGCA	p.Gln20_Gln23del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.537_548delACAGCAGCAGCA	p.Gln180_Gln183del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.57_68delACAGCAGCAGCA	p.Gln20_Gln23del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes AF: 0.000595 AC: 88 AN: 148004 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00206

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000266 AC: 30 AN: 112582 AF XY: 0.000306

Gnomad AFR exome AF: 0.000977

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00149

Gnomad FIN exome AF: 0.000128

Gnomad NFE exome AF: 0.0000240

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000108 AC: 146 AN: 1354802 Hom.: 0 AF XY: 0.000106 AC XY: 71 AN XY: 668402

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

African (AFR) AF: 0.00123 AC: 35 AN: 28494

American (AMR) AF: 0.000212 AC: 7 AN: 33080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24402

East Asian (EAS) AF: 0.00194 AC: 63 AN: 32394

South Asian (SAS) AF: 0.000316 AC: 24 AN: 76018

European-Finnish (FIN) AF: 0.0000267 AC: 1 AN: 37454

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4120

European-Non Finnish (NFE) AF: 0.00000659 AC: 7 AN: 1062564

Other (OTH) AF: 0.000142 AC: 8 AN: 56276

⚠️ 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: 0.000601 AC: 89 AN: 148108 Hom.: 0 Cov.: 30 AF XY: 0.000703 AC XY: 51 AN XY: 72516

African (AFR) AF: 0.00180 AC: 72 AN: 40080

American (AMR) AF: 0.000134 AC: 2 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00206 AC: 10 AN: 4844

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10278

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66510

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00295 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=180/20	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: rs746198949; hg19: chr12-112036770; COSMIC: COSV101112572; COSMIC: COSV101112572;