12-6936728-A-G

Variant names:

• chr12-6936728-A-G
• rs150855426
• NM_001940.4:c.1461A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001940.4(ATN1):​c.1461A>G​(p.Gln487Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 145,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.381
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 12-6936728-A-G is Benign according to our data. Variant chr12-6936728-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210373.
• BP7: Synonymous conserved (PhyloP=-0.381 with no splicing effect.
• BS2: High AC in GnomAd4 at 60 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATN1	NM_001940.4	MANE Select	c.1461A>G	p.Gln487Gln	synonymous	Exon 5 of 10	NP_001931.2
	ATN1	NM_001007026.2		c.1461A>G	p.Gln487Gln	synonymous	Exon 5 of 10	NP_001007027.1
	ATN1	NM_001424176.1		c.1461A>G	p.Gln487Gln	synonymous	Exon 5 of 10	NP_001411105.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATN1	ENST00000396684.3	TSL:1 MANE Select	c.1461A>G	p.Gln487Gln	synonymous	Exon 5 of 10	ENSP00000379915.2
	ATN1	ENST00000356654.8	TSL:1	c.1461A>G	p.Gln487Gln	synonymous	Exon 5 of 10	ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 61 AN: 145030 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000936

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000422

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000992

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000330

Gnomad OTH AF: 0.00102

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000257 AC: 370 AN: 1438912 Hom.: 0 Cov.: 59 AF XY: 0.000260 AC XY: 186 AN XY: 716730

African (AFR) AF: 0.000465 AC: 15 AN: 32226

American (AMR) AF: 0.000598 AC: 24 AN: 40114

Ashkenazi Jewish (ASJ) AF: 0.0000779 AC: 2 AN: 25686

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38780

South Asian (SAS) AF: 0.000164 AC: 14 AN: 85558

European-Finnish (FIN) AF: 0.0000951 AC: 5 AN: 52578

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5722

European-Non Finnish (NFE) AF: 0.000253 AC: 278 AN: 1098784

Other (OTH) AF: 0.000420 AC: 25 AN: 59464

GnomAD4 genome AF: 0.000413 AC: 60 AN: 145130 Hom.: 0 Cov.: 21 AF XY: 0.000312 AC XY: 22 AN XY: 70472

African (AFR) AF: 0.000516 AC: 20 AN: 38762

American (AMR) AF: 0.000935 AC: 13 AN: 13898

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

East Asian (EAS) AF: 0.000424 AC: 2 AN: 4722

South Asian (SAS) AF: 0.00 AC: 0 AN: 4430

European-Finnish (FIN) AF: 0.0000992 AC: 1 AN: 10080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000330 AC: 22 AN: 66702

Other (OTH) AF: 0.00101 AC: 2 AN: 1984

Alfa AF: 0.0594 Hom.: 83

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATN1: BP4, BP7

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.3
DANN	Benign	0.45
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs150855426; hg19: chr12-7045891; COSMIC: COSV63110302; COSMIC: COSV63110302;