12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr12-6936728-ACAGCAGCAG-A
• rs60216939
• NM_001940.4:c.1500_1508delGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001940.4(ATN1):​c.1500_1508delGCAGCAGCA​(p.Gln500_Gln502del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0314 in 1,583,048 control chromosomes in the GnomAD database, including 1,748 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.081 (1075 hom., cov: 0)
  • Exomes 𝑓: 0.026 (673 hom.)
• Consequence: ATN1 NM_001940.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.09
• Publications: 8 publications found

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]

ATN1 Gene-Disease associations (from GenCC):

• congenital hypotonia, epilepsy, developmental delay, and digital anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dentatorubral-pallidoluysian atrophy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 12-6936728-ACAGCAGCAG-A is Benign according to our data. Variant chr12-6936728-ACAGCAGCAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1285148.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1500_1508delGCAGCAGCA	p.Gln500_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENST00000396684.3	NP_001931.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3	c.1500_1508delGCAGCAGCA	p.Gln500_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1500_1508delGCAGCAGCA	p.Gln500_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 11766 AN: 144852 Hom.: 1067 Cov.: 0

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00450

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.0351

Gnomad SAS AF: 0.0714

Gnomad FIN AF: 0.00853

Gnomad MID AF: 0.0355

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0674

GnomAD4 exome AF: 0.0263 AC: 37875 AN: 1438100 Hom.: 673 AF XY: 0.0274 AC XY: 19596 AN XY: 716348

African (AFR) AF: 0.224 AC: 7068 AN: 31602

American (AMR) AF: 0.0764 AC: 3065 AN: 40100

Ashkenazi Jewish (ASJ) AF: 0.0486 AC: 1248 AN: 25676

East Asian (EAS) AF: 0.0300 AC: 1165 AN: 38776

South Asian (SAS) AF: 0.0719 AC: 6147 AN: 85530

European-Finnish (FIN) AF: 0.00921 AC: 484 AN: 52572

Middle Eastern (MID) AF: 0.0510 AC: 292 AN: 5720

European-Non Finnish (NFE) AF: 0.0147 AC: 16167 AN: 1098696

Other (OTH) AF: 0.0377 AC: 2239 AN: 59428

GnomAD4 genome AF: 0.0814 AC: 11805 AN: 144948 Hom.: 1075 Cov.: 0 AF XY: 0.0801 AC XY: 5640 AN XY: 70386

African (AFR) AF: 0.231 AC: 8918 AN: 38618

American (AMR) AF: 0.0638 AC: 886 AN: 13888

Ashkenazi Jewish (ASJ) AF: 0.0459 AC: 155 AN: 3374

East Asian (EAS) AF: 0.0345 AC: 163 AN: 4720

South Asian (SAS) AF: 0.0715 AC: 316 AN: 4420

European-Finnish (FIN) AF: 0.00853 AC: 86 AN: 10080

Middle Eastern (MID) AF: 0.0382 AC: 11 AN: 288

European-Non Finnish (NFE) AF: 0.0170 AC: 1135 AN: 66694

Other (OTH) AF: 0.0662 AC: 131 AN: 1978

Alfa AF: 0.0118 Hom.: 123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=188/12	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs60216939; hg19: chr12-7045891; COSMIC: COSV63111054; COSMIC: COSV63111054;