12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAG

Position:

• chr12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001940.4(ATN1):​c.1497_1508del​(p.Gln499_Gln502del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00764 in 1,582,352 control chromosomes in the GnomAD database, including 166 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.020 (78 hom., cov: 0)
  • Exomes 𝑓: 0.0064 (88 hom.)
• Consequence: ATN1 NM_001940.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 4.09

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10	ENST00000396684.3	NP_001931.2
ATN1	NM_001007026.2	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10		NP_001007027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10	1	NM_001940.4	ENSP00000379915	P1
ATN1	ENST00000356654.8	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10	1		ENSP00000349076	P1

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 2894 AN: 145004 Hom.: 78 Cov.: 0

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.000889

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.00293

Gnomad FIN AF: 0.000397

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.0199

GnomAD4 exome AF: 0.00640 AC: 9193 AN: 1437248 Hom.: 88 AF XY: 0.00623 AC XY: 4462 AN XY: 715876

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.00978

Gnomad4 ASJ exome AF: 0.000390

Gnomad4 EAS exome AF: 0.0386

Gnomad4 SAS exome AF: 0.00406

Gnomad4 FIN exome AF: 0.000590

Gnomad4 NFE exome AF: 0.00391

Gnomad4 OTH exome AF: 0.00882

GnomAD4 genome AF: 0.0200 AC: 2896 AN: 145104 Hom.: 78 Cov.: 0 AF XY: 0.0198 AC XY: 1392 AN XY: 70462

Gnomad4 AFR AF: 0.0596

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.000889

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.00316

Gnomad4 FIN AF: 0.000397

Gnomad4 NFE AF: 0.00399

Gnomad4 OTH AF: 0.0197

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 31, 2021

ACMG classification criteria: PM2 -

ATN1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

This variant is classified as likely 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;