12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2
The NM_001940.4(ATN1):c.1464_1508dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln488_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 0.000034 ( 0 hom., cov: 0)
Exomes 𝑓: 0.000019 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ATN1
NM_001940.4 disruptive_inframe_insertion
NM_001940.4 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.621
Publications
8 publications found
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 anomaliesInheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- dentatorubral-pallidoluysian atrophyInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
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 5 AD gene.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATN1 | ENST00000396684.3 | c.1464_1508dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA | p.Gln488_Gln502dup | disruptive_inframe_insertion | Exon 5 of 10 | 1 | NM_001940.4 | ENSP00000379915.2 | ||
| ATN1 | ENST00000356654.8 | c.1464_1508dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA | p.Gln488_Gln502dup | disruptive_inframe_insertion | Exon 5 of 10 | 1 | ENSP00000349076.3 |
Frequencies
GnomAD3 genomes 0.0000345 AC: 5AN: 145034Hom.: 0 Cov.: 0 show subpopulations
GnomAD3 genomes
AF:
AC:
5
AN:
145034
Hom.:
Cov.:
0
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000195 AC: 28AN: 1438890Hom.: 0 Cov.: 0 AF XY: 0.0000223 AC XY: 16AN XY: 716720 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
28
AN:
1438890
Hom.:
Cov.:
0
AF XY:
AC XY:
16
AN XY:
716720
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
32226
American (AMR)
AF:
AC:
0
AN:
40114
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25686
East Asian (EAS)
AF:
AC:
20
AN:
38762
South Asian (SAS)
AF:
AC:
2
AN:
85554
European-Finnish (FIN)
AF:
AC:
0
AN:
52578
Middle Eastern (MID)
AF:
AC:
0
AN:
5722
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1098782
Other (OTH)
AF:
AC:
2
AN:
59466
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.311
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000345 AC: 5AN: 145034Hom.: 0 Cov.: 0 AF XY: 0.0000142 AC XY: 1AN XY: 70354 show subpopulations
GnomAD4 genome
AF:
AC:
5
AN:
145034
Hom.:
Cov.:
0
AF XY:
AC XY:
1
AN XY:
70354
show subpopulations
African (AFR)
AF:
AC:
1
AN:
38648
American (AMR)
AF:
AC:
0
AN:
13890
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3376
East Asian (EAS)
AF:
AC:
3
AN:
4734
South Asian (SAS)
AF:
AC:
0
AN:
4434
European-Finnish (FIN)
AF:
AC:
0
AN:
10080
Middle Eastern (MID)
AF:
AC:
0
AN:
310
European-Non Finnish (NFE)
AF:
AC:
0
AN:
66710
Other (OTH)
AF:
AC:
1
AN:
1964
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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