12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_001940.4(ATN1):c.1503_1508dupGCAGCA(p.Gln501_Gln502dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H503H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.049 ( 220 hom., cov: 0)

Exomes 𝑓: 0.061 ( 603 hom. )

Failed GnomAD Quality Control

Consequence

ATN1
NM_001940.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.621

Publications

8 publications found

Variant links:

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)

ATN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant 12-6936728-A-ACAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210377.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4 link	c.1503_1508dupGCAGCA	p.Gln501_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	ENST00000396684.3	NP_001931.2	P54259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3 link	c.1503_1508dupGCAGCA	p.Gln501_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2		P54259
ATN1	ENST00000356654.8 link	c.1503_1508dupGCAGCA	p.Gln501_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1		ENSP00000349076.3		P54259

Frequencies

GnomAD3 genomes

AF:

0.0485

AC:

7037

AN:

144952

Hom.:

219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.0892

Gnomad AMR

AF:

0.0464

Gnomad ASJ

AF:

0.0376

Gnomad EAS

AF:

0.176

Gnomad SAS

AF:

0.0697

Gnomad FIN

AF:

0.0205

Gnomad MID

AF:

0.0258

Gnomad NFE

AF:

0.0580

Gnomad OTH

AF:

0.0418

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0613

AC:

88020

AN:

1436500

Hom.:

603

Cov.:

AF XY:

0.0614

AC XY:

43919

AN XY:

715504

show subpopulations

African (AFR)

AF:

0.0200

AC:

644

AN:

32210

American (AMR)

AF:

0.0378

AC:

1513

AN:

40070

Ashkenazi Jewish (ASJ)

AF:

0.0348

AC:

891

AN:

25640

East Asian (EAS)

AF:

0.175

AC:

6680

AN:

38256

South Asian (SAS)

AF:

0.0697

AC:

5941

AN:

85296

European-Finnish (FIN)

AF:

0.0210

AC:

1102

AN:

52538

Middle Eastern (MID)

AF:

0.0600

AC:

343

AN:

5718

European-Non Finnish (NFE)

AF:

0.0613

AC:

67284

AN:

1097398

Other (OTH)

AF:

0.0610

AC:

3622

AN:

59374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

4654

9307

13961

18614

23268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2668

5336

8004

10672

13340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0485

AC:

7036

AN:

145052

Hom.:

220

Cov.:

AF XY:

0.0473

AC XY:

3329

AN XY:

70426

show subpopulations

African (AFR)

AF:

0.0228

AC:

882

AN:

38742

American (AMR)

AF:

0.0464

AC:

644

AN:

13890

Ashkenazi Jewish (ASJ)

AF:

0.0376

AC:

127

AN:

3374

East Asian (EAS)

AF:

0.176

AC:

831

AN:

4716

South Asian (SAS)

AF:

0.0697

AC:

308

AN:

4418

European-Finnish (FIN)

AF:

0.0205

AC:

207

AN:

10076

Middle Eastern (MID)

AF:

0.0243

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0580

AC:

3870

AN:

66678

Other (OTH)

AF:

0.0408

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

286

573

859

1146

1432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0192

Hom.:

123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Mar 20, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Normal variation in repetative sequence -

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 19, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20977674, 15148151, 23263592, 8136840) -

Dentatorubral-pallidoluysian atrophy

Benign:1

Sep 28, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over