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Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001940.4(ATN1):​c.1488_1508del​(p.Gln496_Gln502del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.112 in 1,583,744 control chromosomes in the GnomAD database, including 9,431 homozygotes. Variant has been reported in ClinVar as Uncertain significance (β˜…β˜…). Synonymous variant affecting the same amino acid position (i.e. Q488Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.097 ( 728 hom., cov: 0)
Exomes 𝑓: 0.11 ( 8703 hom. )

Consequence

ATN1
NM_001940.4 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 4.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATN1NM_001940.4 linkuse as main transcriptc.1488_1508del p.Gln496_Gln502del inframe_deletion 5/10 ENST00000396684.3
ATN1NM_001007026.2 linkuse as main transcriptc.1488_1508del p.Gln496_Gln502del inframe_deletion 5/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATN1ENST00000396684.3 linkuse as main transcriptc.1488_1508del p.Gln496_Gln502del inframe_deletion 5/101 NM_001940.4 P1
ATN1ENST00000356654.8 linkuse as main transcriptc.1488_1508del p.Gln496_Gln502del inframe_deletion 5/101 P1

Frequencies

GnomAD3 genomes
AF:
0.0966
AC:
14000
AN:
144970
Hom.:
727
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.0594
Gnomad AMI
AF:
0.188
Gnomad AMR
AF:
0.0940
Gnomad ASJ
AF:
0.136
Gnomad EAS
AF:
0.0277
Gnomad SAS
AF:
0.125
Gnomad FIN
AF:
0.0722
Gnomad MID
AF:
0.211
Gnomad NFE
AF:
0.121
Gnomad OTH
AF:
0.117
GnomAD4 exome
AF:
0.114
AC:
163947
AN:
1438672
Hom.:
8703
AF XY:
0.115
AC XY:
82161
AN XY:
716576
show subpopulations
Gnomad4 AFR exome
AF:
0.0599
Gnomad4 AMR exome
AF:
0.0711
Gnomad4 ASJ exome
AF:
0.131
Gnomad4 EAS exome
AF:
0.0196
Gnomad4 SAS exome
AF:
0.121
Gnomad4 FIN exome
AF:
0.0770
Gnomad4 NFE exome
AF:
0.121
Gnomad4 OTH exome
AF:
0.114
GnomAD4 genome
AF:
0.0965
AC:
14001
AN:
145072
Hom.:
728
Cov.:
0
AF XY:
0.0949
AC XY:
6685
AN XY:
70442
show subpopulations
Gnomad4 AFR
AF:
0.0594
Gnomad4 AMR
AF:
0.0938
Gnomad4 ASJ
AF:
0.136
Gnomad4 EAS
AF:
0.0278
Gnomad4 SAS
AF:
0.125
Gnomad4 FIN
AF:
0.0722
Gnomad4 NFE
AF:
0.121
Gnomad4 OTH
AF:
0.119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The ATN1 p.Gln496_Gln502del variant was not identified in the dbSNP or LOVD 3.0 databases, however it was identified in the Clinvar and Cosmic databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant was identified in the homozygous form in two children from a consanguineous family presenting with severe, global developmental delay, however the cause of their developmental delay was attributed to biallelic variants in CAMK2A (Chia_2018_PMID: 29784083). This variant is an in-frame deletion resulting in the removal of 7 glutamine (gln) residues at codon 496, within a glutamine repeat region. The insertion of (CAG)n or glutamine repeats has been found to cause dentatorubro-pallidoluysian atrophy, however this variant is a (CAG)n repeat deletion within the normal range considered of 6-35 repeats (Koide_1994_PMID: 8136840; MIM: 607462). The impact of this alteration on ATN1 protein function is not known, however MutationTaster predicts this variant to be a polymorphism. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 20, 2020Variant summary: ATN1 c.1488_1508del21 (p.Gln496_Gln502del) results in an in-frame deletion that is predicted to remove seven amino acids from the encoded protein. The variant was absent in 247226 control chromosomes, however the variant is located in a highly variable region, with many del/dups present in gnomad. Dentatorubral-pallidoluysian atrophy (DRPLA) results from an increased number of copies (expansion) of the CAG trinucleotide repeat in the ATN1 gene (Genetics Home Reference Page), whereas other types of mutations may be related to other ATN1-related disorders. c.1488_1508del21 has been reported in the literature in at least one individual for which whole exome sequencing detected causitive mutations other than the variant of interest (Chia_2018). This report does not provide unequivocal conclusions about association of the variant with DRPLA or other ATN1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as a VUS. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs60216939; hg19: chr12-7045891; API