chr6-16362511-C-T

Variant names:

• chr6-16362511-C-T
• rs179971
• NM_001128164.2:c.-160-34041G>A

Variant summary

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

The NM_001128164.2(ATXN1):​c.-160-34041G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 151,744 control chromosomes in the GnomAD database, including 34,711 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 0.67 (34711 hom., cov: 30)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 14 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-160-34041G>A		intron_variant	Intron 6 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-160-34041G>A		intron_variant	Intron 7 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-189-34041G>A		intron_variant	Intron 7 of 8		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.-160-34041G>A		intron_variant	Intron 6 of 7	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.-160-34041G>A		intron_variant	Intron 7 of 8	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.666 AC: 100982 AN: 151624 Hom.: 34690 Cov.: 30

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.694

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

GnomAD4 genome AF: 0.666 AC: 101044 AN: 151744 Hom.: 34711 Cov.: 30 AF XY: 0.668 AC XY: 49535 AN XY: 74168

African (AFR) AF: 0.471 AC: 19468 AN: 41298

American (AMR) AF: 0.785 AC: 11973 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2303 AN: 3468

East Asian (EAS) AF: 0.682 AC: 3505 AN: 5138

South Asian (SAS) AF: 0.683 AC: 3264 AN: 4780

European-Finnish (FIN) AF: 0.711 AC: 7490 AN: 10540

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.746 AC: 50670 AN: 67948

Other (OTH) AF: 0.698 AC: 1472 AN: 2108

Alfa AF: 0.701 Hom.: 4527

Bravo AF: 0.664

Asia WGS AF: 0.690 AC: 2402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.50
DANN	Benign	0.76
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs179971; hg19: chr6-16362742; COSMIC: COSV55209001;