12-6936728-ACAGCAGCAGCAGCAGCAGCAG-A

Position:

• chr12-6936728-ACAGCAGCAGCAGCAGCAGCAG-A

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 (★★). 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• 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]

ACMG classification

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: 14000 AN: 144970 Hom.: 727 Cov.: 0

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

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

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:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign: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

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs60216939; hg19: chr12-7045891;