rs765632065

Variant names:

• chr1-16987071-AG-A
• rs765632065
• NM_022089.4:c.3057delC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000915371: 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" and additional evidence is available in ClinVar. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.00
• Publications: 21 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Illumina
• autosomal recessive spastic paraplegia type 78

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• parkinsonism due to ATP13A2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915371: 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).; SCV000709790: Published functional studies suggest that c.3057delC has lower steady-state levels of expression compared with wild-type (Tan et al., 2011); SCV002103960: "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)."; SCV003580023: 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).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.3057delC	p.Tyr1020ThrfsTer3	frameshift	Exon 26 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.3042delC	p.Tyr1015ThrfsTer3	frameshift	Exon 26 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.2925delC	p.Tyr976ThrfsTer3	frameshift	Exon 25 of 27	NP_001135446.1	Q9NQ11-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.3057delC	p.Tyr1020ThrfsTer3	frameshift	Exon 26 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.3042delC	p.Tyr1015ThrfsTer3	frameshift	Exon 26 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.2925delC	p.Tyr976ThrfsTer3	frameshift	Exon 25 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152124 Hom.: 0 Cov.: 32

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: 36 AN: 248620 AF XY: 0.000148

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: 97 AN: 1461216 Hom.: 0 Cov.: 61 AF XY: 0.0000660 AC XY: 48 AN XY: 726910

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00256 AC: 67 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111970

Other (OTH) AF: 0.000199 AC: 12 AN: 60384

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.000196 AC: 3 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000128

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Kufor-Rakeb syndrome (3)
2	-	-	Autosomal recessive spastic paraplegia type 78 (2)
2	-	-	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (2)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodegeneration with brain iron accumulation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=5/195	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs765632065;

hg19: chr1-17313566;