chr12-6936728-ACAGCAGCAG-A

Position:

• chr12-6936728-ACAGCAGCAG-A

Variant summary

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

The NM_001940.4(ATN1):​c.1500_1508del​(p.Gln500_Gln502del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0314 in 1,583,048 control chromosomes in the GnomAD database, including 1,748 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 0.081 (1075 hom., cov: 0)
  • Exomes 𝑓: 0.026 (673 hom.)
• Consequence: ATN1 NM_001940.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:2
• 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 (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.1500_1508del	p.Gln500_Gln502del	inframe_deletion	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.1500_1508del	p.Gln500_Gln502del	inframe_deletion	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.1500_1508del	p.Gln500_Gln502del	inframe_deletion	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.1500_1508del	p.Gln500_Gln502del	inframe_deletion	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 11766 AN: 144852 Hom.: 1067 Cov.: 0

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00450

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.0351

Gnomad SAS AF: 0.0714

Gnomad FIN AF: 0.00853

Gnomad MID AF: 0.0355

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0674

GnomAD4 exome AF: 0.0263 AC: 37875 AN: 1438100 Hom.: 673 AF XY: 0.0274 AC XY: 19596 AN XY: 716348

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.0764

Gnomad4 ASJ exome AF: 0.0486

Gnomad4 EAS exome AF: 0.0300

Gnomad4 SAS exome AF: 0.0719

Gnomad4 FIN exome AF: 0.00921

Gnomad4 NFE exome AF: 0.0147

Gnomad4 OTH exome AF: 0.0377

GnomAD4 genome AF: 0.0814 AC: 11805 AN: 144948 Hom.: 1075 Cov.: 0 AF XY: 0.0801 AC XY: 5640 AN XY: 70386

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.0638

Gnomad4 ASJ AF: 0.0459

Gnomad4 EAS AF: 0.0345

Gnomad4 SAS AF: 0.0715

Gnomad4 FIN AF: 0.00853

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0662

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Mar 23, 2020

- -

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;