chr6-16306746-T-C

Position:

• chr6-16306746-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001128164.2(ATXN1):​c.2031A>G​(p.Ser677=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00521 in 1,613,982 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (128 hom.)
• Consequence: ATXN1 NM_001128164.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.90

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-16306746-T-C is Benign according to our data. Variant chr6-16306746-T-C is described in ClinVar as [Benign]. Clinvar id is 3037222.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.2031A>G	p.Ser677=	synonymous_variant	8/8	ENST00000436367.6
ATXN1	NM_000332.4	c.2031A>G	p.Ser677=	synonymous_variant	9/9
ATXN1	NM_001357857.2	c.*1444A>G		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.2031A>G	p.Ser677=	synonymous_variant	8/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.2031A>G	p.Ser677=	synonymous_variant	9/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3253 AN: 152050 Hom.: 96 Cov.: 33

Gnomad AFR AF: 0.0689

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00684 AC: 1719 AN: 251308 Hom.: 42 AF XY: 0.00529 AC XY: 719 AN XY: 135848

Gnomad AFR exome AF: 0.0693

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00353 AC: 5154 AN: 1461814 Hom.: 128 Cov.: 32 AF XY: 0.00322 AC XY: 2340 AN XY: 727196

Gnomad4 AFR exome AF: 0.0737

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.00707

GnomAD4 genome AF: 0.0214 AC: 3250 AN: 152168 Hom.: 96 Cov.: 33 AF XY: 0.0210 AC XY: 1559 AN XY: 74400

Gnomad4 AFR AF: 0.0687

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00888 Hom.: 29

Bravo AF: 0.0245

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATXN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.1
DANN	Benign	0.57

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: rs34324423; hg19: chr6-16306977; COSMIC: COSV55235733;