rs1997716

Variant names:

• chr6-16600448-T-C
• rs1997716
• NM_001128164.2:c.-488-14541A>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.-488-14541A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 152,128 control chromosomes in the GnomAD database, including 40,228 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 0.73 (40228 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 4 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=-0.72).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128164.2. 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
	ATXN1	NM_001128164.2	MANE Select	c.-488-14541A>G		intron	N/A	NP_001121636.1
	ATXN1	NM_000332.4		c.-488-14541A>G		intron	N/A	NP_000323.2
	ATXN1	NM_001357857.2		c.-517-14541A>G		intron	N/A	NP_001344786.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.-488-14541A>G		intron	N/A	ENSP00000416360.1
	ATXN1	ENST00000244769.8	TSL:1	c.-488-14541A>G		intron	N/A	ENSP00000244769.3
	ATXN1	ENST00000473388.6	TSL:1	n.405-14541A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110275 AN: 152012 Hom.: 40186 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.836

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.723

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

GnomAD4 genome AF: 0.726 AC: 110374 AN: 152128 Hom.: 40228 Cov.: 32 AF XY: 0.725 AC XY: 53925 AN XY: 74360

African (AFR) AF: 0.690 AC: 28622 AN: 41492

American (AMR) AF: 0.837 AC: 12794 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2665 AN: 3466

East Asian (EAS) AF: 0.552 AC: 2856 AN: 5172

South Asian (SAS) AF: 0.765 AC: 3688 AN: 4822

European-Finnish (FIN) AF: 0.667 AC: 7051 AN: 10568

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50262 AN: 67994

Other (OTH) AF: 0.722 AC: 1526 AN: 2114

Alfa AF: 0.742 Hom.: 64407

Bravo AF: 0.736

Asia WGS AF: 0.686 AC: 2389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.91
DANN	Benign	0.56
PhyloP100		-1.3
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: rs1997716; hg19: chr6-16600679;