chr12-6936728-ACAG-A

Variant names:

• chr12-6936728-ACAG-A
• rs60216939
• NM_001940.4:c.1506_1508delGCA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001940.4(ATN1):​c.1506_1508delGCA​(p.Gln502del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 1,548,102 control chromosomes in the GnomAD database, including 569 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (151 hom., cov: 0)
  • Exomes 𝑓: 0.045 (418 hom.)
• Consequence: ATN1 NM_001940.4 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.621
• 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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• dentatorubral-pallidoluysian atrophy

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-6936728-ACAG-A is Benign according to our data. Variant chr12-6936728-ACAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1174682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

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.1506_1508delGCA	p.Gln502del	disruptive_inframe_deletion	Exon 5 of 10	NP_001931.2	P54259
	ATN1	NM_001007026.2		c.1506_1508delGCA	p.Gln502del	disruptive_inframe_deletion	Exon 5 of 10	NP_001007027.1	P54259
	ATN1	NM_001424176.1		c.1506_1508delGCA	p.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.1506_1508delGCA	p.Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000379915.2	P54259
	ATN1	ENST00000356654.8	TSL:1	c.1506_1508delGCA	p.Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000349076.3	P54259
	ATN1	ENST00000882240.1		c.1506_1508delGCA	p.Gln502del	disruptive_inframe_deletion	Exon 5 of 11	ENSP00000552299.1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6069 AN: 144946 Hom.: 152 Cov.: 0

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.0429

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0788

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0871

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0480

GnomAD4 exome AF: 0.0455 AC: 63789 AN: 1403058 Hom.: 418 AF XY: 0.0472 AC XY: 32931 AN XY: 698220

African (AFR) AF: 0.0357 AC: 1143 AN: 32016

American (AMR) AF: 0.0395 AC: 1487 AN: 37630

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 1186 AN: 24460

East Asian (EAS) AF: 0.0106 AC: 406 AN: 38150

South Asian (SAS) AF: 0.0847 AC: 7015 AN: 82830

European-Finnish (FIN) AF: 0.0212 AC: 1058 AN: 49798

Middle Eastern (MID) AF: 0.0808 AC: 455 AN: 5628

European-Non Finnish (NFE) AF: 0.0449 AC: 48310 AN: 1075032

Other (OTH) AF: 0.0474 AC: 2729 AN: 57514

GnomAD4 genome AF: 0.0419 AC: 6073 AN: 145044 Hom.: 151 Cov.: 0 AF XY: 0.0406 AC XY: 2862 AN XY: 70440

African (AFR) AF: 0.0371 AC: 1438 AN: 38736

American (AMR) AF: 0.0430 AC: 597 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 152 AN: 3376

East Asian (EAS) AF: 0.0136 AC: 64 AN: 4720

South Asian (SAS) AF: 0.0789 AC: 349 AN: 4426

European-Finnish (FIN) AF: 0.0156 AC: 157 AN: 10072

Middle Eastern (MID) AF: 0.0833 AC: 24 AN: 288

European-Non Finnish (NFE) AF: 0.0455 AC: 3035 AN: 66666

Other (OTH) AF: 0.0475 AC: 94 AN: 1980

Alfa AF: 0.0206 Hom.: 123

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	ATN1-related disorder (1)
-	-	1	Dentatorubral-pallidoluysian atrophy;C5193125:Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs60216939; hg19: chr12-7045891; COSMIC: COSV63111029; COSMIC: COSV63111029;