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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
The NM_001940.4(ATN1):βc.1488_1508delβ(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: π 0.097 ( 728 hom., cov: 0)
Exomes π: 0.11 ( 8703 hom. )
Consequence
ATN1
NM_001940.4 inframe_deletion
NM_001940.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.09
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]
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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 |
---|---|---|---|---|---|---|---|
ATN1 | NM_001940.4 | c.1488_1508del | p.Gln496_Gln502del | inframe_deletion | 5/10 | ENST00000396684.3 | |
ATN1 | NM_001007026.2 | c.1488_1508del | p.Gln496_Gln502del | inframe_deletion | 5/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATN1 | ENST00000396684.3 | c.1488_1508del | p.Gln496_Gln502del | inframe_deletion | 5/10 | 1 | NM_001940.4 | P1 | |
ATN1 | ENST00000356654.8 | c.1488_1508del | p.Gln496_Gln502del | inframe_deletion | 5/10 | 1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0966 AC: 14000AN: 144970Hom.: 727 Cov.: 0
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GnomAD4 exome AF: 0.114 AC: 163947AN: 1438672Hom.: 8703 AF XY: 0.115 AC XY: 82161AN XY: 716576
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GnomAD4 genome AF: 0.0965 AC: 14001AN: 145072Hom.: 728 Cov.: 0 AF XY: 0.0949 AC XY: 6685AN XY: 70442
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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 provided | clinical testing | Department 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 submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 20, 2020 | Variant 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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at