rs12204969

Variant names:

• chr6-16693946-T-C
• rs12204969
• NM_001128164.2:c.-614-36045A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128164.2(ATXN1):​c.-614-36045A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0998 in 152,224 control chromosomes in the GnomAD database, including 835 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (835 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.788
• Publications: 5 publications found

Genes affected

ATXN1 (HGNC:10548): (ataxin 1) The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). Alternative splicing results in multiple transcript variants, with one variant encoding multiple distinct proteins, ATXN1 and Alt-ATXN1, due to the use of overlapping alternate reading frames. [provided by RefSeq, Nov 2017]

ATXN1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-614-36045A>G		intron_variant	Intron 2 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-614-36045A>G		intron_variant	Intron 3 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-643-36045A>G		intron_variant	Intron 3 of 8		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.-614-36045A>G		intron_variant	Intron 2 of 7	1	NM_001128164.2	ENSP00000416360.1

Frequencies

GnomAD3 genomes AF: 0.0998 AC: 15174 AN: 152108 Hom.: 832 Cov.: 32

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.0838

Gnomad ASJ AF: 0.0623

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0926

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0998 AC: 15193 AN: 152224 Hom.: 835 Cov.: 32 AF XY: 0.0995 AC XY: 7406 AN XY: 74438

African (AFR) AF: 0.0768 AC: 3191 AN: 41536

American (AMR) AF: 0.0837 AC: 1280 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 216 AN: 3468

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5180

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4830

European-Finnish (FIN) AF: 0.146 AC: 1543 AN: 10596

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8316 AN: 67998

Other (OTH) AF: 0.0917 AC: 194 AN: 2116

Alfa AF: 0.112 Hom.: 1924

Bravo AF: 0.0955

Asia WGS AF: 0.0290 AC: 102 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.40
DANN	Benign	0.83
PhyloP100		-0.79
Mutation Taster		=100/0	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: rs12204969; hg19: chr6-16694177;