Genetic Variant ATXN2:p.Gln21_Gln24dup (chr12-111598963-C-CTGCTGCTGCTGT) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_001372574.1(ATXN2):c.71_72insACAGCAGCAGCA(p.Gln21_Gln24dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 148,664 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 60 hom. )

Failed GnomAD Quality Control

Consequence

ATXN2
NM_001372574.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.421

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001372574.1

BP6

Variant 12-111598963-C-CTGCTGCTGCTGT is Benign according to our data. Variant chr12-111598963-C-CTGCTGCTGCTGT is described in ClinVar as [Benign]. Clinvar id is 2643323.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 1718 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1 link	c.71_72insACAGCAGCAGCA	p.Gln21_Gln24dup	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.71_72insACAGCAGCAGCA	p.Gln21_Gln24dup	disruptive_inframe_insertion	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1		A0A5F9ZI57

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1717

AN:

148558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.00221

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.00550

Gnomad EAS

AF:

0.000604

Gnomad SAS

AF:

0.00230

Gnomad FIN

AF:

0.0245

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.00884

GnomAD3 exomes

AF:

0.00604

AC:

673

AN:

111432

Hom.:

AF XY:

0.00536

AC XY:

330

AN XY:

61544

show subpopulations

Gnomad AFR exome

AF:

0.00132

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.00741

Gnomad OTH exome

AF:

0.00671

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00777

AC:

10433

AN:

1342940

Hom.:

Cov.:

AF XY:

0.00761

AC XY:

5045

AN XY:

662678

show subpopulations

Gnomad4 AFR exome

AF:

0.00243

Gnomad4 AMR exome

AF:

0.00834

Gnomad4 ASJ exome

AF:

0.00423

Gnomad4 EAS exome

AF:

0.000763

Gnomad4 SAS exome

AF:

0.00340

Gnomad4 FIN exome

AF:

0.0233

Gnomad4 NFE exome

AF:

0.00800

Gnomad4 OTH exome

AF:

0.00742

GnomAD4 genome

AF:

0.0116

AC:

1718

AN:

148664

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

862

AN XY:

72718

show subpopulations

Gnomad4 AFR

AF:

0.00571

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.00550

Gnomad4 EAS

AF:

0.000807

Gnomad4 SAS

AF:

0.00230

Gnomad4 FIN

AF:

0.0245

Gnomad4 NFE

AF:

0.0154

Gnomad4 OTH

AF:

0.00875

Alfa

AF:

0.00565

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATXN2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over