12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr12-6936728-ACAGCAGCAGCAGCAG-A
• rs60216939
• NM_001940.4:c.1494_1508delGCAGCAGCAGCAGCA

Variant summary

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

The NM_001940.4(ATN1):​c.1494_1508delGCAGCAGCAGCAGCA​(p.Gln498_Gln502del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.112 in 1,583,772 control chromosomes in the GnomAD database, including 7,674 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.095 (871 hom., cov: 0)
  • Exomes 𝑓: 0.11 (6803 hom.)
• Consequence: ATN1 NM_001940.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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-ACAGCAGCAGCAGCAG-A is Benign according to our data. Variant chr12-6936728-ACAGCAGCAGCAGCAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1050478.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1494_1508delGCAGCAGCAGCAGCA	p.Gln498_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.1494_1508delGCAGCAGCAGCAGCA	p.Gln498_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1494_1508delGCAGCAGCAGCAGCA	p.Gln498_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.0951 AC: 13793 AN: 144976 Hom.: 869 Cov.: 0

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0597

Gnomad AMR AF: 0.0887

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0419

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.113 AC: 163219 AN: 1438696 Hom.: 6803 AF XY: 0.111 AC XY: 79674 AN XY: 716618

African (AFR) AF: 0.0199 AC: 641 AN: 32176

American (AMR) AF: 0.0648 AC: 2600 AN: 40110

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 1169 AN: 25686

East Asian (EAS) AF: 0.157 AC: 6069 AN: 38728

South Asian (SAS) AF: 0.0489 AC: 4185 AN: 85554

European-Finnish (FIN) AF: 0.158 AC: 8330 AN: 52556

Middle Eastern (MID) AF: 0.0448 AC: 256 AN: 5720

European-Non Finnish (NFE) AF: 0.122 AC: 133794 AN: 1098712

Other (OTH) AF: 0.104 AC: 6175 AN: 59454

GnomAD4 genome AF: 0.0951 AC: 13791 AN: 145076 Hom.: 871 Cov.: 0 AF XY: 0.0957 AC XY: 6743 AN XY: 70440

African (AFR) AF: 0.0275 AC: 1065 AN: 38758

American (AMR) AF: 0.0884 AC: 1228 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.0459 AC: 155 AN: 3376

East Asian (EAS) AF: 0.182 AC: 861 AN: 4722

South Asian (SAS) AF: 0.0530 AC: 235 AN: 4430

European-Finnish (FIN) AF: 0.175 AC: 1760 AN: 10072

Middle Eastern (MID) AF: 0.0417 AC: 12 AN: 288

European-Non Finnish (NFE) AF: 0.123 AC: 8233 AN: 66668

Other (OTH) AF: 0.0954 AC: 189 AN: 1982

Alfa AF: 0.111 Hom.: 123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATN1 p.Gln498_Gln502del variant was not identified in the literature nor was it identified in the MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs377147612), ClinVar and Cosmic. The variant was identified in control databases in 41 of 259998 chromosomes at a frequency of 0.000158 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 19 of 20928 chromosomes (freq: 0.000908), Other in 2 of 6794 chromosomes (freq: 0.000294), Latino in 9 of 31612 chromosomes (freq: 0.000285), East Asian in 3 of 16812 chromosomes (freq: 0.000178) and European (non-Finnish) in 8 of 122724 chromosomes (freq: 0.000065), while the variant was not observed in the Ashkenazi Jewish, European (Finnish) and South Asian populations. This variant is an in-frame deletion resulting in the removal of 5 glutamine (gln) residues at codon 498, within a glutamine repeat region. The insertion of (CAG)n or glutamine repeats has been found to cause dentatorubro-pallidoluysian atrophy, however this variant is a (CAG)n repeat deletion within the normal range of 6-35 repeats (Koide_1994_PMID: 8136840; MIM: 607462). The impact of this alteration on ATN1 protein function is not known, however MutationTaster predicts this variant to be a polymorphism. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=175/25	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: COSV63110197; COSMIC: COSV63110197;