chr1-16987071-AG-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_022089.4(ATP13A2):c.3057delC(p.Tyr1020ThrfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

ATP13A2
NM_022089.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.00

Publications

20 publications found

Variant links:

Genes affected

ATP13A2 (HGNC:30213): (ATPase cation transporting 13A2) This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]

ATP13A2 Gene-Disease associations (from GenCC):

Kufor-Rakeb syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, G2P, ClinGen
autosomal recessive spastic paraplegia type 78
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
parkinsonism due to ATP13A2 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ATP13A2 links:

ENSG00000226526 (HGNC:):

ENSG00000226526 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-16987071-AG-A is Pathogenic according to our data. Variant chr1-16987071-AG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 465253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4 link	c.3057delC	p.Tyr1020ThrfsTer3	frameshift_variant	Exon 26 of 29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13 link	c.3057delC	p.Tyr1020ThrfsTer3	frameshift_variant	Exon 26 of 29	1	NM_022089.4	ENSP00000327214.8		Q9NQ11-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000145

AC:

AN:

248620

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461216

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00256

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111970

Other (OTH)

AF:

0.000199

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.000196

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000434

Hom.:

Bravo

AF:

0.000128

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kufor-Rakeb syndrome

Pathogenic:3

Jan 07, 2020

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3057delC variant has been previously reported as disease-causing in PMIDs 22296644, 21724849, 29966207, 16964263, 21665991. -

Aug 26, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP13A2 c.3057delC (p.Tyr1020ThrfsTer3) variant is a frameshift variant and is predicted to result in a premature termination of the protein. The variant has been reported in a compound heterozygous state in four siblings of a large non-consanguineous Chilean family with Kufor-Rakeb syndrome (Ramirez et al. 2006). The variant segregates with disease in this family over two generations, with three unaffected siblings and the mother carrying the p.Tyr1020ThrfsTer3 variant in a heterozygous state. Further evaluation of this same family by Bruggemann et al. (2010) showed that the p.Tyr1020ThrfsTer3 variant in single heterozygous state may be a risk allele for later onset Parkinsonism. Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregate Consortium. Functional studies demonstrated that the p.Tyr1020ThrfsTer3 variant protein is mislocalized to the endoplasmic reticulum and is targeted for degradation via the proteasome (Ramirez et al. 2006; Ugolino et al. 2011; Podhajska et al. 2012). Based on the available evidence and the potential impact of frameshift variants, the p.Tyr1020ThrfsTer3 variant is classified as likely pathogenic for Kufor-Rakeb syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78

Pathogenic:2

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr1020Thrfs*3) in the ATP13A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP13A2 are known to be pathogenic (PMID: 16964263, 21696388). This variant is present in population databases (rs765632065, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with Kufor-Rakeb syndrome (KRS) (PMID: 16964263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 465253). For these reasons, this variant has been classified as Pathogenic. -

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive spastic paraplegia type 78

Pathogenic:2

Jun 30, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2022

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Oct 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_moderate, PS3, PS4_moderate, PVS1 -

Dec 14, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in association with Kufor-Rakeb syndrome in a family where affected individuals were compound heterozygous for the c.3057delC variant and another variant (Ramirez et al., 2006); Published functional studies suggest that c.3057delC has lower steady-state levels of expression compared with wild-type (Tan et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21696388, 21665991, 21724849, 22296644, 16964263, 29966207, 31692161, 31980526, 35180557) -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Feb 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATP13A2 c.3057delC (p.Tyr1020ThrfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 248620 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP13A2 causing Neurodegeneration With Brain Iron Accumulation/Kufor-Rakeb syndrome (0.00014 vs 0.00019), allowing no conclusion about variant significance. c.3057delC has been reported in the literature in multiple individuals affected with Neurodegeneration associated with Kufor-Rakeb syndrome (example, Ramirez_2006, Inzelberg_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating that this mutant is unstable and localizes in the endoplasmic reticulum (ER), does not reach the lysosome, is cytotoxic and hypersensitizes cells to ER-stress induced cell-death (example, Ugolio_2011). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Sep 09, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3057delC (p.Y1020Tfs*3) alteration, located in exon 26 (coding exon 26) of the ATP13A2 gene, consists of a deletion of one nucleotide at position 3057, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in trans with a second ATP13A2 alteration in patients with features of Kufor-Rakeb syndrome, including early-onset Parkinson's disease, and has been shown to segregate with disease in multiple families (Ramirez, 2006; Behrens, 2010; Brüggemann, 2010; Inzelberg, 2018). Functional studies in patient-derived cells suggest this alteration results in loss of function due to impaired localization and degradation in the ER (Ramirez, 2006; Tan, 2011; Ugolino, 2011; Podhajska, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over