6-16326380-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001128164.2(ATXN1):c.1917+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,611,262 control chromosomes in the GnomAD database, including 1,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.050 (479 hom., cov: 32)
  • Exomes 𝑓: 0.013 (583 hom.)
• Consequence: ATXN1 NM_001128164.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.69

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-16326380-C-A is Benign according to our data. Variant chr6-16326380-C-A is described in ClinVar as [Benign]. Clinvar id is 1304636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.1917+14G>T		intron_variant		ENST00000436367.6
ATXN1	NM_000332.4	c.1917+14G>T		intron_variant
ATXN1	NM_001357857.2	c.*1330+14G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.1917+14G>T		intron_variant		1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.1917+14G>T		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7506 AN: 152110 Hom.: 471 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.00731

Gnomad SAS AF: 0.00914

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00841

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0203 AC: 5059 AN: 249326 Hom.: 214 AF XY: 0.0176 AC XY: 2379 AN XY: 134862

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.00620

Gnomad SAS exome AF: 0.00938

Gnomad FIN exome AF: 0.00742

Gnomad NFE exome AF: 0.00912

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0125 AC: 18250 AN: 1459034 Hom.: 583 Cov.: 33 AF XY: 0.0123 AC XY: 8892 AN XY: 725580

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0450

Gnomad4 EAS exome AF: 0.00595

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.00636

Gnomad4 NFE exome AF: 0.00719

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0495 AC: 7538 AN: 152228 Hom.: 479 Cov.: 32 AF XY: 0.0480 AC XY: 3573 AN XY: 74430

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.00733

Gnomad4 SAS AF: 0.00873

Gnomad4 FIN AF: 0.00640

Gnomad4 NFE AF: 0.00841

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0240 Hom.: 33

Bravo AF: 0.0550

Asia WGS AF: 0.0160 AC: 57 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

GeneDx

Jun 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.0060
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72840240; hg19: chr6-16326611; COSMIC: COSV104392054; COSMIC: COSV104392054;