12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAG

Variant names:

• chr12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-A
• rs60216939
• NM_001940.4:c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001940.4(ATN1):​c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA​(p.Gln492_Gln502del) variant causes a disruptive inframe deletion change. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000098 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• 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, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• dentatorubral-pallidoluysian atrophy

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001940.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATN1	NM_001940.4	MANE Select	c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln492_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	NP_001931.2	P54259
	ATN1	NM_001007026.2		c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln492_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	NP_001007027.1	P54259
	ATN1	NM_001424176.1		c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln492_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	NP_001411105.1	P54259

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATN1	ENST00000396684.3	TSL:1 MANE Select	c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln492_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000379915.2	P54259
	ATN1	ENST00000356654.8	TSL:1	c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln492_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000349076.3	P54259
	ATN1	ENST00000882240.1		c.1476_1508delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln492_Gln502del	disruptive_inframe_deletion	Exon 5 of 11	ENSP00000552299.1

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 15 AN: 145034 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000980 AC: 141 AN: 1438920 Hom.: 0 AF XY: 0.0000991 AC XY: 71 AN XY: 716734

African (AFR) AF: 0.0000310 AC: 1 AN: 32226

American (AMR) AF: 0.0000499 AC: 2 AN: 40114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 38780

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52578

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5722

European-Non Finnish (NFE) AF: 0.000117 AC: 129 AN: 1098790

Other (OTH) AF: 0.000101 AC: 6 AN: 59466

GnomAD4 genome AF: 0.000103 AC: 15 AN: 145034 Hom.: 0 Cov.: 0 AF XY: 0.0000853 AC XY: 6 AN XY: 70354

African (AFR) AF: 0.000155 AC: 6 AN: 38648

American (AMR) AF: 0.00 AC: 0 AN: 13890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4734

South Asian (SAS) AF: 0.00 AC: 0 AN: 4434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000135 AC: 9 AN: 66710

Other (OTH) AF: 0.00 AC: 0 AN: 1964

Alfa AF: 0.00 Hom.: 123

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=169/31	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;