6-16741802-C-T

Variant names:

• chr6-16741802-C-T
• rs697739
• NM_001128164.2:c.-615+11431G>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+11431G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 152,160 control chromosomes in the GnomAD database, including 15,679 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 0.43 (15679 hom., cov: 33)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81
• Publications: 18 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.-615+11431G>A		intron_variant	Intron 2 of 7	ENST00000436367.6	NP_001121636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.-615+11431G>A		intron_variant	Intron 2 of 7	1	NM_001128164.2	ENSP00000416360.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64720 AN: 152042 Hom.: 15659 Cov.: 33

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.426 AC: 64787 AN: 152160 Hom.: 15679 Cov.: 33 AF XY: 0.428 AC XY: 31805 AN XY: 74380

African (AFR) AF: 0.620 AC: 25744 AN: 41502

American (AMR) AF: 0.447 AC: 6840 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1274 AN: 3472

East Asian (EAS) AF: 0.778 AC: 4027 AN: 5178

South Asian (SAS) AF: 0.452 AC: 2177 AN: 4814

European-Finnish (FIN) AF: 0.276 AC: 2924 AN: 10588

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20446 AN: 68004

Other (OTH) AF: 0.425 AC: 897 AN: 2110

Alfa AF: 0.363 Hom.: 36428

Bravo AF: 0.454

Asia WGS AF: 0.625 AC: 2175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.54
DANN	Benign	0.54
PhyloP100		-1.8
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: rs697739; hg19: chr6-16742033;