Genetic Variant ATN1:p.Gln493_Gln502del (chr12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001940.4(ATN1):c.1479_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln493_Gln502del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000369 in 1,584,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

ATN1
NM_001940.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4 link	c.1479_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln493_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.1479_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln493_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2		P54259
ATN1	ENST00000356654.8 link	c.1479_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln493_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1		ENSP00000349076.3		P54259

Frequencies

GnomAD3 genomes

AF:

0.000365

AC:

AN:

145034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000845

Gnomad SAS

AF:

0.000226

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000570

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000370

AC:

532

AN:

1438918

Hom.:

AF XY:

0.000384

AC XY:

275

AN XY:

716732

show subpopulations

African (AFR)

AF:

0.000310

AC:

AN:

32226

American (AMR)

AF:

0.000374

AC:

AN:

40114

Ashkenazi Jewish (ASJ)

AF:

0.000234

AC:

AN:

25686

East Asian (EAS)

AF:

0.000129

AC:

AN:

38780

South Asian (SAS)

AF:

0.000175

AC:

AN:

85558

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52578

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.000423

AC:

465

AN:

1098788

Other (OTH)

AF:

0.000219

AC:

AN:

59466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000365

AC:

AN:

145134

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

AN XY:

70474

show subpopulations

African (AFR)

AF:

0.000155

AC:

AN:

38764

American (AMR)

AF:

0.000288

AC:

AN:

13900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3376

East Asian (EAS)

AF:

0.000847

AC:

AN:

4722

South Asian (SAS)

AF:

0.000226

AC:

AN:

4430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000570

AC:

AN:

66702

Other (OTH)

AF:

0.00

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.1

Mutation Taster

=166/34

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

Computational scores

Splicing

Publications

Other links and lift over