Genetic Variant ATXN2:p.Gln19dup (chr12-111598978-T-TTGC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001372574.1(ATXN2):c.54_56dupGCA(p.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 0.0011 in 137,636 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 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATXN2
NM_001372574.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.273

Publications

2 publications found

Variant links:

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 links:

ATXN2-AS (HGNC:51838): (ATXN2 antisense RNA)

ATXN2-AS links:

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ACMG classification

Classification was made for transcript

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 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1 link	c.54_56dupGCA	p.Gln19dup	disruptive_inframe_insertion	Exon 1 of 25	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1 link	c.54_56dupGCA	p.Gln19dup	disruptive_inframe_insertion	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

152

AN:

137564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000344

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00194

Gnomad ASJ

AF:

0.000311

Gnomad EAS

AF:

0.000230

Gnomad SAS

AF:

0.000231

Gnomad FIN

AF:

0.000583

Gnomad MID

AF:

0.00352

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00107

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00105

AC:

1213

AN:

1154180

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

574

AN XY:

567646

show subpopulations

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

African (AFR)

AF:

0.000482

AC:

AN:

24906

American (AMR)

AF:

0.00107

AC:

AN:

27166

Ashkenazi Jewish (ASJ)

AF:

0.0000453

AC:

AN:

22082

East Asian (EAS)

AF:

0.0000384

AC:

AN:

26040

South Asian (SAS)

AF:

0.000186

AC:

AN:

59210

European-Finnish (FIN)

AF:

0.000841

AC:

AN:

32110

Middle Eastern (MID)

AF:

0.00148

AC:

AN:

3380

European-Non Finnish (NFE)

AF:

0.00117

AC:

1070

AN:

911300

Other (OTH)

AF:

0.00119

AC:

AN:

47986

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.339

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00110

AC:

152

AN:

137636

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

66994

show subpopulations

African (AFR)

AF:

0.000344

AC:

AN:

37836

American (AMR)

AF:

0.00194

AC:

AN:

13916

Ashkenazi Jewish (ASJ)

AF:

0.000311

AC:

AN:

3214

East Asian (EAS)

AF:

0.000230

AC:

AN:

4340

South Asian (SAS)

AF:

0.000231

AC:

AN:

4322

European-Finnish (FIN)

AF:

0.000583

AC:

AN:

8572

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.00162

AC:

101

AN:

62442

Other (OTH)

AF:

0.00106

AC:

AN:

1884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.27

Mutation Taster

=84/16

polymorphism

(source)

Splicing

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

Publications

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12-111598978-TTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over