12-111599196-G-C

Variant names:

• chr12-111599196-G-C
• rs695871
• ENST00000550104.5:c.319C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000550104.5(ATXN2):​c.319C>G​(p.Leu107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,209,904 control chromosomes in the GnomAD database, including 341,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (31645 hom., cov: 29)
  • Exomes 𝑓: 0.75 (309828 hom.)
• Consequence: ATXN2 ENST00000550104.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.0670
• Publications: 43 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.9935905E-7).
• BP6: Variant 12-111599196-G-C is Benign according to our data. Variant chr12-111599196-G-C is described in ClinVar as Benign. ClinVar VariationId is 128507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000550104.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.-162C>G		5_prime_UTR	Exon 1 of 25	NP_001359503.1
	ATXN2	NR_132311.2		n.120C>G		non_coding_transcript_exon	Exon 1 of 24
	ATXN2	NM_002973.4		c.-162C>G		5_prime_UTR	Exon 1 of 25	NP_002964.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000550104.5	TSL:1	c.319C>G	p.Leu107Val	missense	Exon 1 of 25	ENSP00000446576.2
	ATXN2	ENST00000483311.6	TSL:1	n.-162C>G		non_coding_transcript_exon	Exon 1 of 24	ENSP00000446512.2
	ATXN2	ENST00000673436.1	MANE Select	c.-162C>G		5_prime_UTR	Exon 1 of 25	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.607 AC: 90782 AN: 149450 Hom.: 31655 Cov.: 29

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.871

Gnomad EAS AF: 0.0926

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.610

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.615

GnomAD2 exomes AF: 0.773 AC: 167 AN: 216 AF XY: 0.754

Gnomad AMR exome AF: 0.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 0.754 AC: 799904 AN: 1060356 Hom.: 309828 Cov.: 61 AF XY: 0.757 AC XY: 379834 AN XY: 501958

African (AFR) AF: 0.296 AC: 6411 AN: 21642

American (AMR) AF: 0.575 AC: 4298 AN: 7470

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 11427 AN: 13080

East Asian (EAS) AF: 0.140 AC: 3299 AN: 23506

South Asian (SAS) AF: 0.649 AC: 12777 AN: 19700

European-Finnish (FIN) AF: 0.814 AC: 16930 AN: 20786

Middle Eastern (MID) AF: 0.641 AC: 1777 AN: 2772

European-Non Finnish (NFE) AF: 0.785 AC: 713936 AN: 909652

Other (OTH) AF: 0.696 AC: 29049 AN: 41748

GnomAD4 genome AF: 0.607 AC: 90784 AN: 149548 Hom.: 31645 Cov.: 29 AF XY: 0.607 AC XY: 44304 AN XY: 72962

African (AFR) AF: 0.309 AC: 12704 AN: 41150

American (AMR) AF: 0.578 AC: 8708 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 2983 AN: 3426

East Asian (EAS) AF: 0.0931 AC: 468 AN: 5026

South Asian (SAS) AF: 0.631 AC: 3021 AN: 4790

European-Finnish (FIN) AF: 0.824 AC: 8250 AN: 10018

Middle Eastern (MID) AF: 0.612 AC: 175 AN: 286

European-Non Finnish (NFE) AF: 0.785 AC: 52418 AN: 66814

Other (OTH) AF: 0.618 AC: 1287 AN: 2082

Alfa AF: 0.685 Hom.: 4765

Bravo AF: 0.572

ExAC AF: 0.389 AC: 6426

Asia WGS AF: 0.421 AC: 1302 AN: 3094

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Spinocerebellar ataxia type 2 Benign:1

Feb 07, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.067
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.11
Sift	Benign	0.32	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.37
ClinPred		0.040	T
GERP RS		0.69
PromoterAI		-0.0044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

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: rs695871; hg19: chr12-112037000; COSMIC: COSV66485453; COSMIC: COSV66485453;