12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAG-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001940.4(ATN1):c.1485_1508delGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln495_Gln502del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00152 in 1,581,842 control chromosomes in the GnomAD database, including 14 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 14 hom. )

Consequence

ATN1
NM_001940.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.09

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 -12 ACMG points.

BP6

Variant 12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAG-A is Benign according to our data. Variant chr12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 2642646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4 link	c.1485_1508delGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln495_Gln502del	disruptive_inframe_deletion	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.1485_1508delGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln495_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2		P54259
ATN1	ENST00000356654.8 link	c.1485_1508delGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln495_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1		ENSP00000349076.3		P54259

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

225

AN:

145032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00267

Gnomad EAS

AF:

0.0104

Gnomad SAS

AF:

0.00271

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0290

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.00153

GnomAD4 exome

AF:

0.00152

AC:

2180

AN:

1436710

Hom.:

AF XY:

0.00160

AC XY:

1146

AN XY:

715582

show subpopulations

African (AFR)

AF:

0.000683

AC:

AN:

32214

American (AMR)

AF:

0.00132

AC:

AN:

40066

Ashkenazi Jewish (ASJ)

AF:

0.00336

AC:

AN:

25612

East Asian (EAS)

AF:

0.0120

AC:

464

AN:

38772

South Asian (SAS)

AF:

0.00471

AC:

402

AN:

85358

European-Finnish (FIN)

AF:

0.0000381

AC:

AN:

52540

Middle Eastern (MID)

AF:

0.00876

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.000881

AC:

966

AN:

1097062

Other (OTH)

AF:

0.00227

AC:

135

AN:

59376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.00156

AC:

226

AN:

145132

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

118

AN XY:

70474

show subpopulations

African (AFR)

AF:

0.000258

AC:

AN:

38764

American (AMR)

AF:

0.00424

AC:

AN:

13900

Ashkenazi Jewish (ASJ)

AF:

0.00267

AC:

AN:

3376

East Asian (EAS)

AF:

0.0104

AC:

AN:

4720

South Asian (SAS)

AF:

0.00271

AC:

AN:

4430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10080

Middle Eastern (MID)

AF:

0.0347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00111

AC:

AN:

66702

Other (OTH)

AF:

0.00151

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

123

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

Inborn genetic diseases

Benign:1

Dec 20, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATN1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.1

Mutation Taster

=155/45

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