6-16567942-C-G

Variant names:

• chr6-16567942-C-G
• rs236949
• NM_001128164.2:c.-361+17838G>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.-361+17838G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 152,010 control chromosomes in the GnomAD database, including 27,541 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 0.60 (27541 hom., cov: 32)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.733
• 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)

ENSG00000309429 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-361+17838G>C		intron_variant	Intron 4 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.-361+17838G>C		intron_variant	Intron 5 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.-390+17838G>C		intron_variant	Intron 5 of 8		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.-361+17838G>C		intron_variant	Intron 4 of 7	1	NM_001128164.2	ENSP00000416360.1

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91120 AN: 151892 Hom.: 27502 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.590

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

GnomAD4 genome AF: 0.600 AC: 91207 AN: 152010 Hom.: 27541 Cov.: 32 AF XY: 0.602 AC XY: 44761 AN XY: 74300

African (AFR) AF: 0.573 AC: 23764 AN: 41470

American (AMR) AF: 0.689 AC: 10531 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2218 AN: 3472

East Asian (EAS) AF: 0.736 AC: 3806 AN: 5172

South Asian (SAS) AF: 0.698 AC: 3370 AN: 4828

European-Finnish (FIN) AF: 0.592 AC: 6236 AN: 10536

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39172 AN: 67942

Other (OTH) AF: 0.596 AC: 1256 AN: 2108

Alfa AF: 0.437 Hom.: 1102

Bravo AF: 0.608

Asia WGS AF: 0.717 AC: 2492 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.8
DANN	Benign	0.47
PhyloP100		0.73
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: rs236949; hg19: chr6-16568173;