6-16326380-C-A

Variant names:

• chr6-16326380-C-A
• rs72840240
• NM_001128164.2:c.1917+14G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.1917+14G>T		intron_variant	Intron 7 of 7	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.1917+14G>T		intron_variant	Intron 8 of 8		NP_000323.2
ATXN1	NM_001357857.2	c.*1330+14G>T		intron_variant	Intron 8 of 8		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.1917+14G>T		intron_variant	Intron 7 of 7	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.1917+14G>T		intron_variant	Intron 8 of 8	1		ENSP00000244769.3

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

GnomAD2 exomes AF: 0.0203 AC: 5059 AN: 249326 AF XY: 0.0176

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 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

African (AFR) AF: 0.163 AC: 5465 AN: 33432

American (AMR) AF: 0.0140 AC: 627 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 1175 AN: 26102

East Asian (EAS) AF: 0.00595 AC: 236 AN: 39672

South Asian (SAS) AF: 0.0108 AC: 928 AN: 86222

European-Finnish (FIN) AF: 0.00636 AC: 332 AN: 52176

Middle Eastern (MID) AF: 0.0422 AC: 243 AN: 5758

European-Non Finnish (NFE) AF: 0.00719 AC: 7984 AN: 1110670

Other (OTH) AF: 0.0209 AC: 1260 AN: 60320

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

African (AFR) AF: 0.150 AC: 6216 AN: 41502

American (AMR) AF: 0.0224 AC: 342 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.00733 AC: 38 AN: 5184

South Asian (SAS) AF: 0.00873 AC: 42 AN: 4810

European-Finnish (FIN) AF: 0.00640 AC: 68 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00841 AC: 572 AN: 68024

Other (OTH) AF: 0.0482 AC: 102 AN: 2114

Alfa AF: 0.0234 Hom.: 55

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

Jun 25, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0060
DANN	Benign	0.56
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs72840240; hg19: chr6-16326611; COSMIC: COSV104392054;