12-111598942-G-GGGC

Variant names:

• chr12-111598942-G-GGGC
• rs749703424
• NM_001372574.1:c.90_92dupGCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PM4_Supporting BP6_Moderate BS2

The NM_001372574.1(ATXN2):​c.90_92dupGCC​(p.Pro31dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,461,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.985

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001372574.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 12-111598942-G-GGGC is Benign according to our data. Variant chr12-111598942-G-GGGC is described in ClinVar as [Benign]. Clinvar id is 2643321.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.90_92dupGCC	p.Pro31dup	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	c.90_92dupGCC	p.Pro31dup	disruptive_inframe_insertion	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 24 AN: 101758 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00335

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000300 AC: 25 AN: 83364 Hom.: 0 AF XY: 0.000423 AC XY: 20 AN XY: 47254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000576

Gnomad ASJ exome AF: 0.000898

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000969

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 155 AN: 1360086 Hom.: 0 Cov.: 30 AF XY: 0.000146 AC XY: 98 AN XY: 671002

Gnomad4 AFR exome AF: 0.000207

Gnomad4 AMR exome AF: 0.0000298

Gnomad4 ASJ exome AF: 0.000985

Gnomad4 EAS exome AF: 0.0000304

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000197

Gnomad4 OTH exome AF: 0.0000707

GnomAD4 genome AF: 0.000236 AC: 24 AN: 101850 Hom.: 0 Cov.: 31 AF XY: 0.000330 AC XY: 16 AN XY: 48412

Gnomad4 AFR AF: 0.000310

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00336

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749703424; hg19: chr12-112036746;