rs2075974

Positions:

• chr6-16327099-T-C
• chr6-16327099-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001128164.2(ATXN1):​c.1212A>G​(p.Glu404Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,613,450 control chromosomes in the GnomAD database, including 49,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.29 (7123 hom., cov: 32)
  • Exomes 𝑓: 0.23 (42722 hom.)
• Consequence: ATXN1 NM_001128164.2 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0320

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 6-16327099-T-C is Benign according to our data. Variant chr6-16327099-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128498.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.032 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.1212A>G	p.Glu404Glu	synonymous_variant	7/8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.1212A>G	p.Glu404Glu	synonymous_variant	8/9		NP_000323.2
ATXN1	NM_001357857.2	c.*625A>G		3_prime_UTR_variant	8/9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.1212A>G	p.Glu404Glu	synonymous_variant	7/8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.1212A>G	p.Glu404Glu	synonymous_variant	8/9	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43462 AN: 151938 Hom.: 7104 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.264 AC: 66340 AN: 250906 Hom.: 10213 AF XY: 0.264 AC XY: 35855 AN XY: 135664

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.503

Gnomad SAS exome AF: 0.368

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.231 AC: 337942 AN: 1461394 Hom.: 42722 Cov.: 91 AF XY: 0.235 AC XY: 170535 AN XY: 727034

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.362

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.286 AC: 43517 AN: 152056 Hom.: 7123 Cov.: 32 AF XY: 0.287 AC XY: 21336 AN XY: 74346

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.479

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.295

Alfa AF: 0.242 Hom.: 3480

Bravo AF: 0.298

Asia WGS AF: 0.466 AC: 1616 AN: 3478

EpiCase AF: 0.205

EpiControl AF: 0.211

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.9
DANN	Benign	0.44

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: rs2075974; hg19: chr6-16327330; COSMIC: COSV55211111; COSMIC: COSV55211111;