12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

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

The NM_001940.4(ATN1):c.1506_1508dupGCA(p.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 0.14 ( 1640 hom., cov: 0)

Exomes 𝑓: 0.16 ( 4193 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:8

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-ACAG is Benign according to our data. Variant chr12-6936728-A-ACAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599473.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4 link	c.1506_1508dupGCA	p.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.1506_1508dupGCA	p.Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2		P54259
ATN1	ENST00000356654.8 link	c.1506_1508dupGCA	p.Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1		ENSP00000349076.3		P54259

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

19678

AN:

144842

Hom.:

1642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0420

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.0550

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.129

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.162

AC:

231434

AN:

1431410

Hom.:

4193

Cov.:

AF XY:

0.162

AC XY:

115448

AN XY:

713010

show subpopulations

African (AFR)

AF:

0.0362

AC:

1165

AN:

32198

American (AMR)

AF:

0.0998

AC:

3999

AN:

40056

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3775

AN:

25634

East Asian (EAS)

AF:

0.0520

AC:

1953

AN:

37522

South Asian (SAS)

AF:

0.157

AC:

13328

AN:

85006

European-Finnish (FIN)

AF:

0.177

AC:

9300

AN:

52412

Middle Eastern (MID)

AF:

0.100

AC:

573

AN:

5706

European-Non Finnish (NFE)

AF:

0.172

AC:

188638

AN:

1093704

Other (OTH)

AF:

0.147

AC:

8703

AN:

59172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

11124

22248

33371

44495

55619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7008

14016

21024

28032

35040

<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:

0.136

AC:

19680

AN:

144942

Hom.:

1640

Cov.:

AF XY:

0.137

AC XY:

9632

AN XY:

70372

show subpopulations

African (AFR)

AF:

0.0419

AC:

1624

AN:

38726

American (AMR)

AF:

0.123

AC:

1705

AN:

13880

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

573

AN:

3374

East Asian (EAS)

AF:

0.0555

AC:

262

AN:

4718

South Asian (SAS)

AF:

0.164

AC:

725

AN:

4422

European-Finnish (FIN)

AF:

0.209

AC:

2103

AN:

10066

Middle Eastern (MID)

AF:

0.167

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.184

AC:

12281

AN:

66600

Other (OTH)

AF:

0.128

AC:

253

AN:

1982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

721

1442

2163

2884

3605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.143

Hom.:

123

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dentatorubral-pallidoluysian atrophy;C5193125:Congenital hypotonia, epilepsy, developmental delay, and digital anomalies

Uncertain:1Benign:1

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 14, 2018

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:2

May 19, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies

Benign:1

Dec 12, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

ATN1-related disorder

Benign:1

Apr 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

(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