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Variant names:

• chr12-6936728-A-ACAG
• rs60216939
• NM_001940.4:c.1506_1508dupGCA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001940.4(ATN1):​c.1506_1508dupGCA​(p.Gln502dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (1640 hom., cov: 0)
  • Exomes 𝑓: 0.16 (4193 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATN1 NM_001940.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• 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 -9 ACMG points.

• BP6: Variant 12-6936728-A-ACAG is Benign according to our data. Variant chr12-6936728-A-ACAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599473.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.1506_1508dupGCA	p.Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	ENST00000396684.3	NP_001931.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3	c.1506_1508dupGCA	p.Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.1506_1508dupGCA	p.Gln502dup	disruptive_inframe_insertion	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes AF: 0.136 AC: 19678 AN: 144842 Hom.: 1642 Cov.: 0

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.162 AC: 231434 AN: 1431410 Hom.: 4193 Cov.: 0 AF XY: 0.162 AC XY: 115448 AN XY: 713010

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.0998

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0520

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.136 AC: 19680 AN: 144942 Hom.: 1640 Cov.: 0 AF XY: 0.137 AC XY: 9632 AN XY: 70372

Gnomad4 AFR AF: 0.0419

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.0555

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.128

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 20, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Normal variation in repetative sequence -

not provided Benign:2

May 19, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dentatorubral-pallidoluysian atrophy;C5193125:Congenital hypotonia, epilepsy, developmental delay, and digital anomalies Uncertain:1

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 12, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

ATN1-related disorder Benign:1

Apr 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;