12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001940.4(ATN1):c.1494_1508dup(p.Gln498_Gln502dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q487Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (11 hom., cov: 0)
  • Exomes 𝑓: 0.010 (107 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.621

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 12-6936728-A-ACAGCAGCAGCAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAGCAGCAGCAG is described in ClinVar as [Benign]. Clinvar id is 2642645.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00854 (1239/145120) while in subpopulation EAS AF= 0.0195 (92/4718). AF 95% confidence interval is 0.0163. There are 11 homozygotes in gnomad4. There are 581 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd at 1239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.1494_1508dup	p.Gln498_Gln502dup	inframe_insertion	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.1494_1508dup	p.Gln498_Gln502dup	inframe_insertion	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.1494_1508dup	p.Gln498_Gln502dup	inframe_insertion	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.1494_1508dup	p.Gln498_Gln502dup	inframe_insertion	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1239 AN: 145020 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.00349

Gnomad AMI AF: 0.0315

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0142

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00926

Gnomad OTH AF: 0.0102

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0105 AC: 15039 AN: 1437896 Hom.: 107 Cov.: 0 AF XY: 0.0106 AC XY: 7613 AN XY: 716196

Gnomad4 AFR exome AF: 0.00301

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.0246

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.00186

Gnomad4 NFE exome AF: 0.00991

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00854 AC: 1239 AN: 145120 Hom.: 11 Cov.: 0 AF XY: 0.00825 AC XY: 581 AN XY: 70464

Gnomad4 AFR AF: 0.00348

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.0142

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00927

Gnomad4 OTH AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ATN1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs60216939; hg19: chr12-7045891;