12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr12-6936728-ACAGCAGCAGCAGCAG-A
• rs60216939
• NM_001940.4:c.1494_1508delGCAGCAGCAGCAGCA

Variant summary

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

The NM_001940.4(ATN1):​c.1494_1508delGCAGCAGCAGCAGCA​(p.Gln498_Gln502del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.112 in 1,583,772 control chromosomes in the GnomAD database, including 7,674 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.095 (871 hom., cov: 0)
  • Exomes 𝑓: 0.11 (6803 hom.)
• Consequence: ATN1 NM_001940.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 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 (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1494_1508delGCAGCAGCAGCAGCA	p.Gln498_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENST00000396684.3	NP_001931.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3	c.1494_1508delGCAGCAGCAGCAGCA	p.Gln498_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1494_1508delGCAGCAGCAGCAGCA	p.Gln498_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.0951 AC: 13793 AN: 144976 Hom.: 869 Cov.: 0

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0597

Gnomad AMR AF: 0.0887

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0419

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.113 AC: 163219 AN: 1438696 Hom.: 6803 AF XY: 0.111 AC XY: 79674 AN XY: 716618

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.0648

Gnomad4 ASJ exome AF: 0.0455

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.0489

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.0951 AC: 13791 AN: 145076 Hom.: 871 Cov.: 0 AF XY: 0.0957 AC XY: 6743 AN XY: 70440

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.0884

Gnomad4 ASJ AF: 0.0459

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.0954

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATN1 p.Gln498_Gln502del variant was not identified in the literature nor was it identified in the MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs377147612), ClinVar and Cosmic. The variant was identified in control databases in 41 of 259998 chromosomes at a frequency of 0.000158 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 19 of 20928 chromosomes (freq: 0.000908), Other in 2 of 6794 chromosomes (freq: 0.000294), Latino in 9 of 31612 chromosomes (freq: 0.000285), East Asian in 3 of 16812 chromosomes (freq: 0.000178) and European (non-Finnish) in 8 of 122724 chromosomes (freq: 0.000065), while the variant was not observed in the Ashkenazi Jewish, European (Finnish) and South Asian populations. This variant is an in-frame deletion resulting in the removal of 5 glutamine (gln) residues at codon 498, 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 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. -

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;