12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q488Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (78 hom., cov: 0)
  • Exomes 𝑓: 0.0064 (88 hom.)
• Consequence: ATN1 NM_001940.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications 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 -9 ACMG points.

• BP6: Variant 12-6936728-ACAGCAGCAGCAG-A is Benign according to our data. Variant chr12-6936728-ACAGCAGCAGCAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1691010.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr12-6936728-ACAGCAGCAGCAG-A is described in Lovd as [Likely_benign]. Variant chr12-6936728-ACAGCAGCAGCAG-A is described in Lovd as [Benign].
• 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	UniProt
ATN1	NM_001940.4	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.1497_1508del	p.Gln499_Gln502del	inframe_deletion	5/10	1		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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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, criteria provided, single submitter

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;