chr12-6936728-ACAGCAG-A

Variant names:

• chr12-6936728-ACAGCAG-A
• rs60216939
• NM_001940.4:c.1503_1508delGCAGCA

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.1503_1508delGCAGCA​(p.Gln501_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 0.0177 in 1,581,786 control chromosomes in the GnomAD database, including 919 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (632 hom., cov: 0)
  • Exomes 𝑓: 0.014 (287 hom.)
• Consequence: ATN1 NM_001940.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• 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-ACAGCAG-A is Benign according to our data. Variant chr12-6936728-ACAGCAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3055682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 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.1503_1508delGCAGCA	p.Gln501_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	NP_001931.2	P54259
	ATN1	NM_001007026.2		c.1503_1508delGCAGCA	p.Gln501_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	NP_001007027.1	P54259
	ATN1	NM_001424176.1		c.1503_1508delGCAGCA	p.Gln501_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.1503_1508delGCAGCA	p.Gln501_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000379915.2	P54259
	ATN1	ENST00000356654.8	TSL:1	c.1503_1508delGCAGCA	p.Gln501_Gln502del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000349076.3	P54259
	ATN1	ENST00000882240.1		c.1503_1508delGCAGCA	p.Gln501_Gln502del	disruptive_inframe_deletion	Exon 5 of 11	ENSP00000552299.1

Frequencies

GnomAD3 genomes AF: 0.0555 AC: 8042 AN: 144894 Hom.: 630 Cov.: 0

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.00741

Gnomad EAS AF: 0.00359

Gnomad SAS AF: 0.0111

Gnomad FIN AF: 0.00625

Gnomad MID AF: 0.0419

Gnomad NFE AF: 0.00926

Gnomad OTH AF: 0.0596

GnomAD4 exome AF: 0.0139 AC: 19913 AN: 1436792 Hom.: 287 AF XY: 0.0133 AC XY: 9538 AN XY: 715488

African (AFR) AF: 0.176 AC: 5676 AN: 32178

American (AMR) AF: 0.0198 AC: 793 AN: 40068

Ashkenazi Jewish (ASJ) AF: 0.00986 AC: 253 AN: 25656

East Asian (EAS) AF: 0.00482 AC: 187 AN: 38776

South Asian (SAS) AF: 0.0103 AC: 878 AN: 84974

European-Finnish (FIN) AF: 0.00756 AC: 397 AN: 52534

Middle Eastern (MID) AF: 0.0328 AC: 187 AN: 5700

European-Non Finnish (NFE) AF: 0.00936 AC: 10268 AN: 1097538

Other (OTH) AF: 0.0215 AC: 1274 AN: 59368

GnomAD4 genome AF: 0.0556 AC: 8063 AN: 144994 Hom.: 632 Cov.: 0 AF XY: 0.0541 AC XY: 3809 AN XY: 70402

African (AFR) AF: 0.174 AC: 6714 AN: 38642

American (AMR) AF: 0.0321 AC: 446 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.00741 AC: 25 AN: 3376

East Asian (EAS) AF: 0.00360 AC: 17 AN: 4718

South Asian (SAS) AF: 0.0111 AC: 49 AN: 4430

European-Finnish (FIN) AF: 0.00625 AC: 63 AN: 10080

Middle Eastern (MID) AF: 0.0451 AC: 13 AN: 288

European-Non Finnish (NFE) AF: 0.00928 AC: 619 AN: 66698

Other (OTH) AF: 0.0585 AC: 116 AN: 1982

Alfa AF: 0.00 Hom.: 123

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ATN1-related disorder (1)
-	-	1	Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=194/6	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; COSMIC: COSV63111110; COSMIC: COSV63111110;