6-16750670-T-C

Variant names:

• chr6-16750670-T-C
• rs649266
• NM_001128164.2:c.-615+2563A>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.-615+2563A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 152,052 control chromosomes in the GnomAD database, including 31,335 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 0.64 (31335 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.807 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	NM_001128164.2	MANE Select	c.-615+2563A>G		intron	N/A	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.-615+2563A>G		intron	N/A	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.-644+2563A>G		intron	N/A	NP_001344786.1	A0A2R8YCF3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.-615+2563A>G		intron	N/A	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.-615+2563A>G		intron	N/A	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000467008.5	TSL:1	n.294+2563A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96626 AN: 151934 Hom.: 31300 Cov.: 32

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.634

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

GnomAD4 genome AF: 0.636 AC: 96706 AN: 152052 Hom.: 31335 Cov.: 32 AF XY: 0.636 AC XY: 47285 AN XY: 74322

African (AFR) AF: 0.743 AC: 30811 AN: 41464

American (AMR) AF: 0.660 AC: 10086 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2184 AN: 3468

East Asian (EAS) AF: 0.827 AC: 4286 AN: 5180

South Asian (SAS) AF: 0.668 AC: 3222 AN: 4826

European-Finnish (FIN) AF: 0.509 AC: 5374 AN: 10562

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38722 AN: 67956

Other (OTH) AF: 0.636 AC: 1343 AN: 2110

Alfa AF: 0.607 Hom.: 15352

Bravo AF: 0.655

Asia WGS AF: 0.715 AC: 2485 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.9
DANN	Benign	0.67
PhyloP100		-0.25
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: rs649266; hg19: chr6-16750901;