12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr12-6936728-A-ACAGCAGCAGCAG
• rs60216939
• NM_001940.4:c.1497_1508dupGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001940.4(ATN1):​c.1497_1508dupGCAGCAGCAGCA​(p.Gln499_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 0.012 (24 hom., cov: 0)
  • Exomes 𝑓: 0.013 (81 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 12-6936728-A-ACAGCAGCAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 3910935.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1497_1508dupGCAGCAGCAGCA	p.Gln499_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.1497_1508dupGCAGCAGCAGCA	p.Gln499_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1497_1508dupGCAGCAGCAGCA	p.Gln499_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1742 AN: 145014 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.00779

Gnomad AMI AF: 0.0180

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00711

Gnomad EAS AF: 0.0640

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.00506

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0158

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0126 AC: 18106 AN: 1437914 Hom.: 81 Cov.: 0 AF XY: 0.0131 AC XY: 9354 AN XY: 716222

African (AFR) AF: 0.00599 AC: 193 AN: 32212

American (AMR) AF: 0.00881 AC: 353 AN: 40072

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 169 AN: 25668

East Asian (EAS) AF: 0.0629 AC: 2431 AN: 38668

South Asian (SAS) AF: 0.0271 AC: 2315 AN: 85486

European-Finnish (FIN) AF: 0.00498 AC: 262 AN: 52566

Middle Eastern (MID) AF: 0.00840 AC: 48 AN: 5716

European-Non Finnish (NFE) AF: 0.0105 AC: 11574 AN: 1098106

Other (OTH) AF: 0.0128 AC: 761 AN: 59420

GnomAD4 genome AF: 0.0120 AC: 1740 AN: 145114 Hom.: 24 Cov.: 0 AF XY: 0.0121 AC XY: 855 AN XY: 70464

African (AFR) AF: 0.00777 AC: 301 AN: 38758

American (AMR) AF: 0.0106 AC: 148 AN: 13898

Ashkenazi Jewish (ASJ) AF: 0.00711 AC: 24 AN: 3376

East Asian (EAS) AF: 0.0640 AC: 302 AN: 4720

South Asian (SAS) AF: 0.0251 AC: 111 AN: 4426

European-Finnish (FIN) AF: 0.00506 AC: 51 AN: 10078

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.0113 AC: 755 AN: 66698

Other (OTH) AF: 0.0156 AC: 31 AN: 1984

Alfa AF: 0.00 Hom.: 123

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

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

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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; COSMIC: COSV63110372; COSMIC: COSV63110372;