12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr12-6936728-A-ACAGCAGCAGCAGCAGCAGCAGCAG
• rs60216939
• NM_001940.4:c.1485_1508dupGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001940.4(ATN1):​c.1485_1508dupGCAGCAGCAGCAGCAGCAGCAGCA​(p.Gln495_Gln502dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H503H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00082 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.621
• 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 -12 ACMG points.

• BP6: Variant 12-6936728-A-ACAGCAGCAGCAGCAGCAGCAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAGCAGCAGCAGCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 3043085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1485_1508dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln495_Gln502dup	disruptive_inframe_insertion	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.1485_1508dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln495_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1485_1508dupGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln495_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 236 AN: 145034 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000432

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00127

Gnomad SAS AF: 0.00316

Gnomad FIN AF: 0.000397

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00153

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000823 AC: 1184 AN: 1438904 Hom.: 0 Cov.: 0 AF XY: 0.000917 AC XY: 657 AN XY: 716722

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000496 AC: 16 AN: 32226

American (AMR) AF: 0.000224 AC: 9 AN: 40114

Ashkenazi Jewish (ASJ) AF: 0.0000779 AC: 2 AN: 25686

East Asian (EAS) AF: 0.00428 AC: 166 AN: 38780

South Asian (SAS) AF: 0.00180 AC: 154 AN: 85558

European-Finnish (FIN) AF: 0.000495 AC: 26 AN: 52576

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5722

European-Non Finnish (NFE) AF: 0.000691 AC: 759 AN: 1098776

Other (OTH) AF: 0.000807 AC: 48 AN: 59466

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00163 AC: 236 AN: 145134 Hom.: 1 Cov.: 0 AF XY: 0.00143 AC XY: 101 AN XY: 70474

African (AFR) AF: 0.00119 AC: 46 AN: 38764

American (AMR) AF: 0.000432 AC: 6 AN: 13900

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3376

East Asian (EAS) AF: 0.00127 AC: 6 AN: 4722

South Asian (SAS) AF: 0.00316 AC: 14 AN: 4430

European-Finnish (FIN) AF: 0.000397 AC: 4 AN: 10080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00234 AC: 156 AN: 66702

Other (OTH) AF: 0.00151 AC: 3 AN: 1984

Alfa AF: 0.00 Hom.: 123

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified 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

- -

ATN1-related disorder Benign:1

Jun 20, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=87/13	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;