Genetic Variant ATN1:p.Gln496_Gln502dup (chr12-6936728-A-ACAGCAGCAGCAGCAGCAGCAG) – 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.1488_1508dupGCAGCAGCAGCAGCAGCAGCA(p.Gln496_Gln502dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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. Synonymous variant affecting the same amino acid position (i.e. H503H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0014 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

ATN1
NM_001940.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4 link	c.1488_1508dupGCAGCAGCAGCAGCAGCAGCA	p.Gln496_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.1488_1508dupGCAGCAGCAGCAGCAGCAGCA	p.Gln496_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2		P54259
ATN1	ENST00000356654.8 link	c.1488_1508dupGCAGCAGCAGCAGCAGCAGCA	p.Gln496_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1		ENSP00000349076.3		P54259

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

332

AN:

145030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00187

Gnomad ASJ

AF:

0.00415

Gnomad EAS

AF:

0.00528

Gnomad SAS

AF:

0.00203

Gnomad FIN

AF:

0.000893

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00234

Gnomad OTH

AF:

0.00204

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00136

AC:

1954

AN:

1438834

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

995

AN XY:

716686

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

32226

American (AMR)

AF:

0.000524

AC:

AN:

40112

Ashkenazi Jewish (ASJ)

AF:

0.00249

AC:

AN:

25684

East Asian (EAS)

AF:

0.00699

AC:

271

AN:

38774

South Asian (SAS)

AF:

0.00219

AC:

187

AN:

85544

European-Finnish (FIN)

AF:

0.000894

AC:

AN:

52578

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00109

AC:

1197

AN:

1098734

Other (OTH)

AF:

0.00203

AC:

121

AN:

59460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

198

298

397

496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00228

AC:

331

AN:

145130

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

149

AN XY:

70472

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

38760

American (AMR)

AF:

0.00187

AC:

AN:

13900

Ashkenazi Jewish (ASJ)

AF:

0.00415

AC:

AN:

3376

East Asian (EAS)

AF:

0.00508

AC:

AN:

4722

South Asian (SAS)

AF:

0.00203

AC:

AN:

4430

European-Finnish (FIN)

AF:

0.000893

AC:

AN:

10080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00234

AC:

156

AN:

66702

Other (OTH)

AF:

0.00202

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

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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12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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