6-16731080-C-T

Variant names:

• chr6-16731080-C-T
• rs10484366
• NM_001128164.2:c.-615+22153G>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.-615+22153G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0471 in 152,232 control chromosomes in the GnomAD database, including 414 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 0.047 (414 hom., cov: 31)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680
• Publications: 2 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-615+22153G>A		intron_variant	Intron 2 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-615+22153G>A		intron_variant	Intron 3 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-644+22153G>A		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.-615+22153G>A		intron_variant	Intron 2 of 7	1	NM_001128164.2	ENSP00000416360.1

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 7173 AN: 152114 Hom.: 417 Cov.: 31

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0464

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

GnomAD4 genome AF: 0.0471 AC: 7168 AN: 152232 Hom.: 414 Cov.: 31 AF XY: 0.0506 AC XY: 3767 AN XY: 74444

African (AFR) AF: 0.0268 AC: 1113 AN: 41532

American (AMR) AF: 0.0549 AC: 840 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 269 AN: 3472

East Asian (EAS) AF: 0.320 AC: 1655 AN: 5174

South Asian (SAS) AF: 0.122 AC: 590 AN: 4826

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10608

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2179 AN: 68008

Other (OTH) AF: 0.0459 AC: 97 AN: 2112

Alfa AF: 0.0374 Hom.: 273

Bravo AF: 0.0506

Asia WGS AF: 0.168 AC: 582 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
DANN	Benign	0.65
PhyloP100		-0.068
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: rs10484366; hg19: chr6-16731311;