Genetic Variant ATN1:p.Gln485_Gln486insGlnGln (chr12-6936716-C-CCAGCAG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001940.4(ATN1):c.1454_1455insGCAGCA(p.Gln485_Gln486insGlnGln) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q485Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATN1
NM_001940.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.13

Publications

0 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
dentatorubral-pallidoluysian atrophy
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ATN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATN1	NM_001940.4	MANE Select	c.1454_1455insGCAGCA	p.Gln485_Gln486insGlnGln	disruptive_inframe_insertion	Exon 5 of 10	NP_001931.2	P54259
ATN1	NM_001007026.2		c.1454_1455insGCAGCA	p.Gln485_Gln486insGlnGln	disruptive_inframe_insertion	Exon 5 of 10	NP_001007027.1	P54259
ATN1	NM_001424176.1		c.1454_1455insGCAGCA	p.Gln485_Gln486insGlnGln	disruptive_inframe_insertion	Exon 5 of 10	NP_001411105.1	P54259

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATN1	ENST00000396684.3	TSL:1 MANE Select	c.1454_1455insGCAGCA	p.Gln485_Gln486insGlnGln	disruptive_inframe_insertion	Exon 5 of 10	ENSP00000379915.2	P54259
ATN1	ENST00000356654.8	TSL:1	c.1454_1455insGCAGCA	p.Gln485_Gln486insGlnGln	disruptive_inframe_insertion	Exon 5 of 10	ENSP00000349076.3	P54259
ATN1	ENST00000882240.1		c.1454_1455insGCAGCA	p.Gln485_Gln486insGlnGln	disruptive_inframe_insertion	Exon 5 of 11	ENSP00000552299.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1440396

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717024

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.00

AC:

AN:

44482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

38606

South Asian (SAS)

AF:

0.00

AC:

AN:

84964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094704

Other (OTH)

AF:

0.00

AC:

AN:

59576

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over