12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr12-6936728-ACAGCAGCAGCAG-A
• rs60216939
• NM_001940.4:c.1497_1508delGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001940.4(ATN1):​c.1497_1508delGCAGCAGCAGCA​(p.Gln499_Gln502del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00764 in 1,582,352 control chromosomes in the GnomAD database, including 166 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q499Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (78 hom., cov: 0)
  • Exomes 𝑓: 0.0064 (88 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
• Publications: 8 publications found

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]

ATN1 Gene-Disease associations (from GenCC):

• congenital hypotonia, epilepsy, developmental delay, and digital anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dentatorubral-pallidoluysian atrophy

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1497_1508delGCAGCAGCAGCA	p.Gln499_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.1497_1508delGCAGCAGCAGCA	p.Gln499_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1497_1508delGCAGCAGCAGCA	p.Gln499_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 2894 AN: 145004 Hom.: 78 Cov.: 0

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.000889

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.00293

Gnomad FIN AF: 0.000397

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.0199

GnomAD4 exome AF: 0.00640 AC: 9193 AN: 1437248 Hom.: 88 AF XY: 0.00623 AC XY: 4462 AN XY: 715876

African (AFR) AF: 0.0650 AC: 2037 AN: 31344

American (AMR) AF: 0.00978 AC: 391 AN: 39972

Ashkenazi Jewish (ASJ) AF: 0.000390 AC: 10 AN: 25648

East Asian (EAS) AF: 0.0386 AC: 1497 AN: 38760

South Asian (SAS) AF: 0.00406 AC: 346 AN: 85172

European-Finnish (FIN) AF: 0.000590 AC: 31 AN: 52570

Middle Eastern (MID) AF: 0.0112 AC: 64 AN: 5720

European-Non Finnish (NFE) AF: 0.00391 AC: 4293 AN: 1098658

Other (OTH) AF: 0.00882 AC: 524 AN: 59404

GnomAD4 genome AF: 0.0200 AC: 2896 AN: 145104 Hom.: 78 Cov.: 0 AF XY: 0.0198 AC XY: 1392 AN XY: 70462

African (AFR) AF: 0.0596 AC: 2309 AN: 38736

American (AMR) AF: 0.0145 AC: 201 AN: 13900

Ashkenazi Jewish (ASJ) AF: 0.000889 AC: 3 AN: 3376

East Asian (EAS) AF: 0.0123 AC: 58 AN: 4722

South Asian (SAS) AF: 0.00316 AC: 14 AN: 4430

European-Finnish (FIN) AF: 0.000397 AC: 4 AN: 10080

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.00399 AC: 266 AN: 66700

Other (OTH) AF: 0.0197 AC: 39 AN: 1984

Alfa AF: 0.00 Hom.: 123

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Mar 31, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 -

ATN1-related disorder Benign:1

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=185/15	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs60216939; hg19: chr12-7045891;