chr12-111485866-C-T

Variant names:

• chr12-111485866-C-T
• rs202116535
• NM_001372574.1:c.2305-1G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001372574.1(ATXN2):​c.2305-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000936 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: ATXN2 NM_001372574.1 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04411765 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.2305-1G>A		splice_acceptor_variant, intron_variant	Intron 16 of 24	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.2305-1G>A		splice_acceptor_variant, intron_variant	Intron 16 of 24		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000156 AC: 39 AN: 249894 AF XY: 0.000163

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000856 AC: 125 AN: 1460888 Hom.: 0 Cov.: 31 AF XY: 0.0000922 AC XY: 67 AN XY: 726724

African (AFR) AF: 0.0000897 AC: 3 AN: 33452

American (AMR) AF: 0.000269 AC: 12 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111566

Other (OTH) AF: 0.000282 AC: 17 AN: 60350

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74450

African (AFR) AF: 0.0000241 AC: 1 AN: 41558

American (AMR) AF: 0.000589 AC: 9 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		5.7
PromoterAI		-0.028	Neutral
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.83		Position offset: -7
DS_AL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs202116535; hg19: chr12-111923670;