12-111598868-G-C

Variant names:

• chr12-111598868-G-C
• rs1433820293
• NM_001372574.1:c.167C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001372574.1(ATXN2):​c.167C>G​(p.Ser56Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,340,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN2 NM_001372574.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0210
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16228694).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372574.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.167C>G	p.Ser56Trp	missense	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.167C>G	p.Ser56Trp	missense	Exon 1 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.-65+707C>G		intron	N/A	NP_001297050.1	Q2M2R5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.167C>G	p.Ser56Trp	missense	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.647C>G	p.Ser216Trp	missense	Exon 1 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.167C>G	p.Ser56Trp	missense	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151370 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1340924 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 661360

African (AFR) AF: 0.00 AC: 0 AN: 27424

American (AMR) AF: 0.00 AC: 0 AN: 31446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23720

East Asian (EAS) AF: 0.00 AC: 0 AN: 30316

South Asian (SAS) AF: 0.00 AC: 0 AN: 75444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059678

Other (OTH) AF: 0.00 AC: 0 AN: 55774

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000661 AC: 1 AN: 151370 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73900

African (AFR) AF: 0.00 AC: 0 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67722

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.021
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.078
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.86	P
Vest4		0.29
MutPred		0.29		Loss of phosphorylation at S216 (P = 9e-04)
MVP		0.38
MPC		0.51
ClinPred		0.17	T
GERP RS		2.4
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.47
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1433820293; hg19: chr12-112036672;