12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001940.4(ATN1):c.1494_1508dupGCAGCAGCAGCAGCA(p.Gln498_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. 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 0.0085 ( 11 hom., cov: 0)

Exomes 𝑓: 0.010 ( 107 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:1

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, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
dentatorubral-pallidoluysian atrophy
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

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-ACAGCAGCAGCAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAGCAGCAGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2642645.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00854 (1239/145120) while in subpopulation EAS AF = 0.0195 (92/4718). AF 95% confidence interval is 0.0163. There are 11 homozygotes in GnomAd4. There are 581 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 1239 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001940.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATN1	NM_001940.4	MANE Select	c.1494_1508dupGCAGCAGCAGCAGCA	p.Gln498_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	NP_001931.2	P54259
ATN1	NM_001007026.2		c.1494_1508dupGCAGCAGCAGCAGCA	p.Gln498_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	NP_001007027.1	P54259
ATN1	NM_001424176.1		c.1494_1508dupGCAGCAGCAGCAGCA	p.Gln498_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	NP_001411105.1	P54259

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATN1	ENST00000396684.3	TSL:1 MANE Select	c.1494_1508dupGCAGCAGCAGCAGCA	p.Gln498_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	ENSP00000379915.2	P54259
ATN1	ENST00000356654.8	TSL:1	c.1494_1508dupGCAGCAGCAGCAGCA	p.Gln498_Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	ENSP00000349076.3	P54259
ATN1	ENST00000882240.1		c.1494_1508dupGCAGCAGCAGCAGCA	p.Gln498_Gln502dup	disruptive_inframe_insertion	Exon 5 of 11	ENSP00000552299.1

Frequencies

GnomAD3 genomes

AF:

0.00854

AC:

1239

AN:

145020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00349

Gnomad AMI

AF:

0.0315

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.0195

Gnomad SAS

AF:

0.0142

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00645

Gnomad NFE

AF:

0.00926

Gnomad OTH

AF:

0.0102

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0105

AC:

15039

AN:

1437896

Hom.:

107

Cov.:

AF XY:

0.0106

AC XY:

7613

AN XY:

716196

show subpopulations

African (AFR)

AF:

0.00301

AC:

AN:

32210

American (AMR)

AF:

0.0134

AC:

535

AN:

40072

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

540

AN:

25656

East Asian (EAS)

AF:

0.0246

AC:

955

AN:

38750

South Asian (SAS)

AF:

0.0147

AC:

1257

AN:

85484

European-Finnish (FIN)

AF:

0.00186

AC:

AN:

52574

Middle Eastern (MID)

AF:

0.00367

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00991

AC:

10878

AN:

1098000

Other (OTH)

AF:

0.0111

AC:

658

AN:

59430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

645

1290

1935

2580

3225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.00854

AC:

1239

AN:

145120

Hom.:

Cov.:

AF XY:

0.00825

AC XY:

581

AN XY:

70464

show subpopulations

African (AFR)

AF:

0.00348

AC:

135

AN:

38762

American (AMR)

AF:

0.0133

AC:

185

AN:

13898

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3374

East Asian (EAS)

AF:

0.0195

AC:

AN:

4718

South Asian (SAS)

AF:

0.0142

AC:

AN:

4428

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10080

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00927

AC:

618

AN:

66702

Other (OTH)

AF:

0.0106

AC:

AN:

1982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00

Hom.:

123

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dentatorubral-pallidoluysian atrophy;C5193125:Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over