rs179994

Positions:

• chr6-16320756-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128164.2(ATXN1):​c.1917+5638T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,200 control chromosomes in the GnomAD database, including 8,095 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 0.31 (8095 hom., cov: 33)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.349

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.1917+5638T>G		intron_variant		ENST00000436367.6
ATXN1	NM_000332.4	c.1917+5638T>G		intron_variant
ATXN1	NM_001357857.2	c.*1330+5638T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.1917+5638T>G		intron_variant		1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.1917+5638T>G		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46544 AN: 152082 Hom.: 8087 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.309

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

GnomAD4 genome AF: 0.306 AC: 46584 AN: 152200 Hom.: 8095 Cov.: 33 AF XY: 0.303 AC XY: 22568 AN XY: 74404

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.305

Alfa AF: 0.363 Hom.: 5916

Bravo AF: 0.303

Asia WGS AF: 0.170 AC: 593 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.44

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: rs179994; hg19: chr6-16320987;