Genetic Variant ATN1:p.Gln497_Gln502del (chr12-6936728-ACAGCAGCAGCAGCAGCAG-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_001940.4(ATN1):c.1491_1508delGCAGCAGCAGCAGCAGCA(p.Gln497_Gln502del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00693 in 1,578,214 control chromosomes in the GnomAD database, including 266 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 0.024 ( 136 hom., cov: 0)

Exomes 𝑓: 0.0052 ( 130 hom. )

Consequence

ATN1
NM_001940.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -10 ACMG points.

BP6

Variant 12-6936728-ACAGCAGCAGCAGCAGCAG-A is Benign according to our data. Variant chr12-6936728-ACAGCAGCAGCAGCAGCAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 3910932.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4 link	c.1491_1508delGCAGCAGCAGCAGCAGCA	p.Gln497_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.1491_1508delGCAGCAGCAGCAGCAGCA	p.Gln497_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2		P54259
ATN1	ENST00000356654.8 link	c.1491_1508delGCAGCAGCAGCAGCAGCA	p.Gln497_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1		ENSP00000349076.3		P54259

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3462

AN:

145000

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0785

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00296

Gnomad EAS

AF:

0.00613

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0000992

Gnomad MID

AF:

0.0226

Gnomad NFE

AF:

0.00192

Gnomad OTH

AF:

0.0224

GnomAD4 exome

AF:

0.00521

AC:

7472

AN:

1433114

Hom.:

130

AF XY:

0.00520

AC XY:

3713

AN XY:

713844

show subpopulations

African (AFR)

AF:

0.0851

AC:

2743

AN:

32216

American (AMR)

AF:

0.00694

AC:

278

AN:

40054

Ashkenazi Jewish (ASJ)

AF:

0.00413

AC:

106

AN:

25660

East Asian (EAS)

AF:

0.00456

AC:

175

AN:

38396

South Asian (SAS)

AF:

0.0132

AC:

1128

AN:

85434

European-Finnish (FIN)

AF:

0.000537

AC:

AN:

52176

Middle Eastern (MID)

AF:

0.0488

AC:

279

AN:

5722

European-Non Finnish (NFE)

AF:

0.00195

AC:

2137

AN:

1094190

Other (OTH)

AF:

0.0101

AC:

598

AN:

59266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

334

668

1003

1337

1671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.0239

AC:

3469

AN:

145100

Hom.:

136

Cov.:

AF XY:

0.0240

AC XY:

1689

AN XY:

70456

show subpopulations

African (AFR)

AF:

0.0785

AC:

3040

AN:

38744

American (AMR)

AF:

0.0103

AC:

143

AN:

13898

Ashkenazi Jewish (ASJ)

AF:

0.00296

AC:

AN:

3376

East Asian (EAS)

AF:

0.00614

AC:

AN:

4720

South Asian (SAS)

AF:

0.0149

AC:

AN:

4430

European-Finnish (FIN)

AF:

0.0000992

AC:

AN:

10076

Middle Eastern (MID)

AF:

0.0243

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00192

AC:

128

AN:

66696

Other (OTH)

AF:

0.0227

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

144

288

433

577

721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:1

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.1

Mutation Taster

=172/28

polymorphism

(source)

Splicing

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

Publications

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12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAG

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