12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr12-6936728-A-ACAGCAGCAG
• rs60216939
• NM_001940.4:c.1500_1508dupGCAGCAGCA

Variant summary

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

The NM_001940.4(ATN1):​c.1500_1508dupGCAGCAGCA​(p.Gln500_Gln502dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. H503H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (77 hom., cov: 0)
  • Exomes 𝑓: 0.019 (83 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 disruptive_inframe_insertion
• Clinical Significance: 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-ACAGCAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAGCAG is described in ClinVar as [Benign]. Clinvar id is 3910933.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1500_1508dupGCAGCAGCA	p.Gln500_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.1500_1508dupGCAGCAGCA	p.Gln500_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1500_1508dupGCAGCAGCA	p.Gln500_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 2966 AN: 145006 Hom.: 76 Cov.: 0

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0468

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0478

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0316

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0185 AC: 26637 AN: 1437720 Hom.: 83 Cov.: 0 AF XY: 0.0193 AC XY: 13793 AN XY: 716096

African (AFR) AF: 0.0142 AC: 458 AN: 32202

American (AMR) AF: 0.0108 AC: 432 AN: 40106

Ashkenazi Jewish (ASJ) AF: 0.0393 AC: 1008 AN: 25668

East Asian (EAS) AF: 0.110 AC: 4227 AN: 38540

South Asian (SAS) AF: 0.0412 AC: 3517 AN: 85404

European-Finnish (FIN) AF: 0.0189 AC: 992 AN: 52564

Middle Eastern (MID) AF: 0.0229 AC: 131 AN: 5718

European-Non Finnish (NFE) AF: 0.0132 AC: 14525 AN: 1098108

Other (OTH) AF: 0.0227 AC: 1347 AN: 59410

GnomAD4 genome AF: 0.0204 AC: 2966 AN: 145106 Hom.: 77 Cov.: 0 AF XY: 0.0221 AC XY: 1560 AN XY: 70466

African (AFR) AF: 0.0144 AC: 559 AN: 38752

American (AMR) AF: 0.0160 AC: 222 AN: 13900

Ashkenazi Jewish (ASJ) AF: 0.0468 AC: 158 AN: 3374

East Asian (EAS) AF: 0.123 AC: 578 AN: 4718

South Asian (SAS) AF: 0.0476 AC: 211 AN: 4430

European-Finnish (FIN) AF: 0.0236 AC: 238 AN: 10076

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.0139 AC: 929 AN: 66696

Other (OTH) AF: 0.0333 AC: 66 AN: 1984

Alfa AF: 0.00 Hom.: 123

ClinVar

Significance: 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: COSV100755643; COSMIC: COSV100755643;