6-16326616-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001128164.2(ATXN1):c.1695G>A(p.Ala565=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,614,076 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (29 hom.)
• Consequence: ATXN1 NM_001128164.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.33

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-16326616-C-T is Benign according to our data. Variant chr6-16326616-C-T is described in ClinVar as [Benign]. Clinvar id is 2656248.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-16326616-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.33 with no splicing effect.
• BS2: High AC in GnomAd at 468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.1695G>A	p.Ala565=	synonymous_variant	7/8	ENST00000436367.6
ATXN1	NM_000332.4	c.1695G>A	p.Ala565=	synonymous_variant	8/9
ATXN1	NM_001357857.2	c.*1108G>A		3_prime_UTR_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.1695G>A	p.Ala565=	synonymous_variant	7/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.1695G>A	p.Ala565=	synonymous_variant	8/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 468 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00414 AC: 1039 AN: 251246 Hom.: 8 AF XY: 0.00437 AC XY: 593 AN XY: 135824

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00568

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.00486

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00413 AC: 6039 AN: 1461786 Hom.: 29 Cov.: 33 AF XY: 0.00417 AC XY: 3029 AN XY: 727186

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00511

Gnomad4 FIN exome AF: 0.00818

Gnomad4 NFE exome AF: 0.00419

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74462

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00726

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00413 Hom.: 1

Bravo AF: 0.00226

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

ATXN1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.28
Dann	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs146373716; hg19: chr6-16326847;