12-6936728-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001940.4(ATN1):c.1491_1508dup(p.Gln497_Gln502dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q487Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0037 (28 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -12 ACMG points.

• BP6: Variant 12-6936728-A-ACAGCAGCAGCAGCAGCAG is Benign according to our data. Variant chr12-6936728-A-ACAGCAGCAGCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 982647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATN1	NM_001940.4	c.1491_1508dup	p.Gln497_Gln502dup	inframe_insertion	5/10	ENST00000396684.3
ATN1	NM_001007026.2	c.1491_1508dup	p.Gln497_Gln502dup	inframe_insertion	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATN1	ENST00000396684.3	c.1491_1508dup	p.Gln497_Gln502dup	inframe_insertion	5/10	1	NM_001940.4	P1
ATN1	ENST00000356654.8	c.1491_1508dup	p.Gln497_Gln502dup	inframe_insertion	5/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 501 AN: 145028 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00410

Gnomad ASJ AF: 0.00622

Gnomad EAS AF: 0.00993

Gnomad SAS AF: 0.00631

Gnomad FIN AF: 0.00298

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00305

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00366 AC: 5261 AN: 1438300 Hom.: 28 Cov.: 0 AF XY: 0.00380 AC XY: 2720 AN XY: 716384

Gnomad4 AFR exome AF: 0.00270

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.00659

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.00706

Gnomad4 FIN exome AF: 0.00211

Gnomad4 NFE exome AF: 0.00308

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00345 AC: 501 AN: 145128 Hom.: 0 Cov.: 0 AF XY: 0.00345 AC XY: 243 AN XY: 70472

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.00410

Gnomad4 ASJ AF: 0.00622

Gnomad4 EAS AF: 0.00995

Gnomad4 SAS AF: 0.00632

Gnomad4 FIN AF: 0.00298

Gnomad4 NFE AF: 0.00300

Gnomad4 OTH AF: 0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

ATN1: BS1 -

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

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;