12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001940.4(ATN1):c.1506_1508dup(p.Gln502dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q487Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1640 hom., cov: 0)
  • Exomes 𝑓: 0.16 (4193 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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 -16 ACMG points.

• BP6: Variant 12-6936728-A-ACAG is Benign according to our data. Variant chr12-6936728-A-ACAG is described in ClinVar as [Likely_benign]. Clinvar id is 599473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.1506_1508dup	p.Gln502dup	inframe_insertion	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.1506_1508dup	p.Gln502dup	inframe_insertion	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.1506_1508dup	p.Gln502dup	inframe_insertion	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.1506_1508dup	p.Gln502dup	inframe_insertion	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 19678 AN: 144842 Hom.: 1642 Cov.: 0

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.162 AC: 231434 AN: 1431410 Hom.: 4193 Cov.: 0 AF XY: 0.162 AC XY: 115448 AN XY: 713010

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.0998

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0520

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.136 AC: 19680 AN: 144942 Hom.: 1640 Cov.: 0 AF XY: 0.137 AC XY: 9632 AN XY: 70372

Gnomad4 AFR AF: 0.0419

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.0555

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dentatorubral-pallidoluysian atrophy;C5193125:Congenital hypotonia, epilepsy, developmental delay, and digital anomalies Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 07, 2021

- -

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies Benign:1

Benign, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 12, 2023

- -

ATN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 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;