12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001940.4(ATN1):c.1503_1508del(p.Gln501_Gln502del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,581,786 control chromosomes in the GnomAD database, including 919 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q488Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (632 hom., cov: 0)
  • Exomes 𝑓: 0.014 (287 hom.)
• Consequence: ATN1 NM_001940.4 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.14

Genes affected

ATN1 (HGNC:3033): (atrophin 1) Dentatorubral pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion from 7-35 copies to 49-93 copies of a trinucleotide repeat (CAG/CAA) within this gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. Alternative splicing results in two transcripts variants that encode the same protein. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 12-6936728-ACAGCAG-A is Benign according to our data. Variant chr12-6936728-ACAGCAG-A is described in ClinVar as [Benign]. Clinvar id is 3055682.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6936728-ACAGCAG-A is described in Lovd as [Benign]. Variant chr12-6936728-ACAGCAG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.1503_1508del	p.Gln501_Gln502del	inframe_deletion	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.1503_1508del	p.Gln501_Gln502del	inframe_deletion	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.1503_1508del	p.Gln501_Gln502del	inframe_deletion	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.1503_1508del	p.Gln501_Gln502del	inframe_deletion	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.0555 AC: 8042 AN: 144894 Hom.: 630 Cov.: 0

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.00741

Gnomad EAS AF: 0.00359

Gnomad SAS AF: 0.0111

Gnomad FIN AF: 0.00625

Gnomad MID AF: 0.0419

Gnomad NFE AF: 0.00926

Gnomad OTH AF: 0.0596

GnomAD4 exome AF: 0.0139 AC: 19913 AN: 1436792 Hom.: 287 AF XY: 0.0133 AC XY: 9538 AN XY: 715488

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.00986

Gnomad4 EAS exome AF: 0.00482

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.00756

Gnomad4 NFE exome AF: 0.00936

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0556 AC: 8063 AN: 144994 Hom.: 632 Cov.: 0 AF XY: 0.0541 AC XY: 3809 AN XY: 70402

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0321

Gnomad4 ASJ AF: 0.00741

Gnomad4 EAS AF: 0.00360

Gnomad4 SAS AF: 0.0111

Gnomad4 FIN AF: 0.00625

Gnomad4 NFE AF: 0.00928

Gnomad4 OTH AF: 0.0585

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs60216939; hg19: chr12-7045891;