12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001940.4(ATN1):c.1503_1508dup(p.Gln501_Gln502dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q487Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.049 (220 hom., cov: 0)
  • Exomes 𝑓: 0.061 (603 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.621

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-A-ACAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210377.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.1503_1508dup	p.Gln501_Gln502dup	inframe_insertion	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.1503_1508dup	p.Gln501_Gln502dup	inframe_insertion	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.1503_1508dup	p.Gln501_Gln502dup	inframe_insertion	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.1503_1508dup	p.Gln501_Gln502dup	inframe_insertion	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7037 AN: 144952 Hom.: 219 Cov.: 0

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.0892

Gnomad AMR AF: 0.0464

Gnomad ASJ AF: 0.0376

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.0418

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0613 AC: 88020 AN: 1436500 Hom.: 603 Cov.: 0 AF XY: 0.0614 AC XY: 43919 AN XY: 715504

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.0378

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.0697

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0613

Gnomad4 OTH exome AF: 0.0610

GnomAD4 genome AF: 0.0485 AC: 7036 AN: 145052 Hom.: 220 Cov.: 0 AF XY: 0.0473 AC XY: 3329 AN XY: 70426

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.0464

Gnomad4 ASJ AF: 0.0376

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.0697

Gnomad4 FIN AF: 0.0205

Gnomad4 NFE AF: 0.0580

Gnomad4 OTH AF: 0.0408

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Mar 20, 2017	Normal variation in repetative sequence -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2020	This variant is associated with the following publications: (PMID: 20977674, 15148151, 23263592, 8136840) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Dentatorubral-pallidoluysian atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Sep 28, 2015

- -

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;