rs2076603

Variant names:

• chr1-16992516-G-A
• rs2076603
• NM_022089.4:c.1815C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16992516-G-A
• chr1-16992516-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022089.4(ATP13A2):​c.1815C>T​(p.Pro605Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,613,888 control chromosomes in the GnomAD database, including 299,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23521 hom., cov: 33)
  • Exomes 𝑓: 0.61 (276426 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0780
• Publications: 27 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: 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

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-16992516-G-A is Benign according to our data. Variant chr1-16992516-G-A is described in ClinVar as Benign. ClinVar VariationId is 128465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.078 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

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.1815C>T	p.Pro605Pro	synonymous	Exon 17 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.1800C>T	p.Pro600Pro	synonymous	Exon 17 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.1800C>T	p.Pro600Pro	synonymous	Exon 17 of 27	NP_001135446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.1815C>T	p.Pro605Pro	synonymous	Exon 17 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.1800C>T	p.Pro600Pro	synonymous	Exon 17 of 29	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.1800C>T	p.Pro600Pro	synonymous	Exon 17 of 27	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83240 AN: 151990 Hom.: 23512 Cov.: 33

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.556 AC: 139819 AN: 251334 AF XY: 0.560

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.545

Gnomad ASJ exome AF: 0.619

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.610 AC: 891678 AN: 1461778 Hom.: 276426 Cov.: 68 AF XY: 0.608 AC XY: 441851 AN XY: 727190

African (AFR) AF: 0.439 AC: 14684 AN: 33480

American (AMR) AF: 0.546 AC: 24410 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 16381 AN: 26136

East Asian (EAS) AF: 0.304 AC: 12080 AN: 39698

South Asian (SAS) AF: 0.519 AC: 44802 AN: 86256

European-Finnish (FIN) AF: 0.548 AC: 29238 AN: 53376

Middle Eastern (MID) AF: 0.619 AC: 3572 AN: 5766

European-Non Finnish (NFE) AF: 0.640 AC: 711167 AN: 1111954

Other (OTH) AF: 0.585 AC: 35344 AN: 60390

GnomAD4 genome AF: 0.547 AC: 83279 AN: 152110 Hom.: 23521 Cov.: 33 AF XY: 0.540 AC XY: 40125 AN XY: 74356

African (AFR) AF: 0.441 AC: 18291 AN: 41498

American (AMR) AF: 0.541 AC: 8260 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2165 AN: 3472

East Asian (EAS) AF: 0.280 AC: 1446 AN: 5164

South Asian (SAS) AF: 0.496 AC: 2390 AN: 4816

European-Finnish (FIN) AF: 0.534 AC: 5650 AN: 10582

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43180 AN: 67984

Other (OTH) AF: 0.548 AC: 1155 AN: 2108

Alfa AF: 0.605 Hom.: 14150

Bravo AF: 0.544

Asia WGS AF: 0.370 AC: 1289 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.623

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Kufor-Rakeb syndrome (2)
-	-	1	Autosomal recessive spastic paraplegia type 78 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.1
DANN	Benign	0.60
PhyloP100		-0.078
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2076603; hg19: chr1-17319011; COSMIC: COSV58700878; COSMIC: COSV58700878;