NM_001128164.2:c.-298-1066T>C

Variant names:

• chr6-16487175-A-G
• rs235147
• NM_001128164.2:c.-298-1066T>C

Variant summary

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

The NM_001128164.2(ATXN1):​c.-298-1066T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 151,912 control chromosomes in the GnomAD database, including 24,896 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 0.57 (24896 hom., cov: 31)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.736 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.-298-1066T>C		intron	N/A	NP_001121636.1
	ATXN1	NM_000332.4		c.-298-1066T>C		intron	N/A	NP_000323.2
	ATXN1	NM_001357857.2		c.-327-1066T>C		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.-298-1066T>C		intron	N/A	ENSP00000416360.1
	ATXN1	ENST00000244769.8	TSL:1	c.-298-1066T>C		intron	N/A	ENSP00000244769.3
	ATXN1	ENST00000473388.6	TSL:1	n.595-1066T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86146 AN: 151794 Hom.: 24852 Cov.: 31

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.560

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

GnomAD4 genome AF: 0.568 AC: 86248 AN: 151912 Hom.: 24896 Cov.: 31 AF XY: 0.579 AC XY: 42959 AN XY: 74246

African (AFR) AF: 0.508 AC: 21042 AN: 41390

American (AMR) AF: 0.682 AC: 10412 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1680 AN: 3470

East Asian (EAS) AF: 0.624 AC: 3224 AN: 5166

South Asian (SAS) AF: 0.756 AC: 3635 AN: 4808

European-Finnish (FIN) AF: 0.642 AC: 6768 AN: 10546

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37729 AN: 67958

Other (OTH) AF: 0.561 AC: 1181 AN: 2106

Alfa AF: 0.563 Hom.: 41496

Bravo AF: 0.564

Asia WGS AF: 0.686 AC: 2384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.43
DANN	Benign	0.28
PhyloP100		-0.021
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: rs235147; hg19: chr6-16487406;