12-111598978-T-C

Variant names:

• chr12-111598978-T-C
• rs76696028
• NM_001372574.1:c.57A>G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001372574.1(ATXN2):​c.57A>G​(p.Gln19Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0441 in 1,222,094 control chromosomes in the GnomAD database, including 2,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1688 hom., cov: 30)
  • Exomes 𝑓: 0.033 (1110 hom.)
• Consequence: ATXN2 NM_001372574.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -2.34

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 12-111598978-T-C is Benign according to our data. Variant chr12-111598978-T-C is described in ClinVar as [Benign]. Clinvar id is 522370.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-111598978-T-C is described in Lovd as [Benign]. Variant chr12-111598978-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.57A>G	p.Gln19Gln	synonymous_variant	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.57A>G	p.Gln19Gln	synonymous_variant	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 17828 AN: 136802 Hom.: 1683 Cov.: 30

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.0772

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.0442

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0461

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.0332 AC: 36052 AN: 1085220 Hom.: 1110 Cov.: 69 AF XY: 0.0331 AC XY: 17736 AN XY: 535156

Gnomad4 AFR exome AF: 0.334

Gnomad4 AMR exome AF: 0.0537

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0202

Gnomad4 SAS exome AF: 0.0439

Gnomad4 FIN exome AF: 0.0306

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.0489

GnomAD4 genome AF: 0.131 AC: 17872 AN: 136874 Hom.: 1688 Cov.: 30 AF XY: 0.126 AC XY: 8400 AN XY: 66630

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.0781

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.0287

Gnomad4 SAS AF: 0.0442

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0473

Gnomad4 OTH AF: 0.102

Alfa AF: 0.115 Hom.: 29

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 2 Benign:1

Mar 28, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.3
DANN	Benign	0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs76696028; hg19: chr12-112036782; COSMIC: COSV66483005; COSMIC: COSV66483005;