6-16513615-T-C

Variant names:

• chr6-16513615-T-C
• rs2237187
• NM_001128164.2:c.-299+9012A>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.-299+9012A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,124 control chromosomes in the GnomAD database, including 1,654 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 0.13 (1654 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 3 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.199 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.-299+9012A>G		intron	N/A	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.-299+9012A>G		intron	N/A	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.-328+9012A>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.-299+9012A>G		intron	N/A	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.-299+9012A>G		intron	N/A	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000473388.6	TSL:1	n.594+9012A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20433 AN: 152006 Hom.: 1651 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.147

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

GnomAD4 genome AF: 0.134 AC: 20437 AN: 152124 Hom.: 1654 Cov.: 32 AF XY: 0.135 AC XY: 10029 AN XY: 74362

African (AFR) AF: 0.0443 AC: 1839 AN: 41500

American (AMR) AF: 0.138 AC: 2113 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 650 AN: 3470

East Asian (EAS) AF: 0.210 AC: 1082 AN: 5162

South Asian (SAS) AF: 0.126 AC: 607 AN: 4818

European-Finnish (FIN) AF: 0.179 AC: 1895 AN: 10582

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11881 AN: 67986

Other (OTH) AF: 0.148 AC: 312 AN: 2112

Alfa AF: 0.160 Hom.: 3423

Bravo AF: 0.126

Asia WGS AF: 0.163 AC: 563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.028
DANN	Benign	0.28
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2237187; hg19: chr6-16513846;