rs200816691

Variant names:

• chr1-17005530-T-C
• rs200816691
• ENST00000617114.5:c.151A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022089.4(ATP13A2):​c.132A>G​(p.Pro44Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,614,116 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (36 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.49
• Publications: 4 publications found

Genes affected

ENSG00000288636 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.073).
• BP6: Variant 1-17005530-T-C is Benign according to our data. Variant chr1-17005530-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00456 (694/152292) while in subpopulation NFE AF = 0.00691 (470/68014). AF 95% confidence interval is 0.00639. There are 3 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.132A>G	p.Pro44Pro	synonymous	Exon 3 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.132A>G	p.Pro44Pro	synonymous	Exon 3 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.132A>G	p.Pro44Pro	synonymous	Exon 3 of 27	NP_001135446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288636	ENST00000617114.5	TSL:5	c.151A>G	p.Met51Val	missense	Exon 3 of 4	ENSP00000478781.2
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.132A>G	p.Pro44Pro	synonymous	Exon 3 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.132A>G	p.Pro44Pro	synonymous	Exon 3 of 29	ENSP00000413307.1

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152174 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00689

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00453 AC: 1133 AN: 250360 AF XY: 0.00445

Gnomad AFR exome AF: 0.000686

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00547

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00629

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00607 AC: 8875 AN: 1461824 Hom.: 36 Cov.: 33 AF XY: 0.00602 AC XY: 4377 AN XY: 727212

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00723 AC: 189 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86258

European-Finnish (FIN) AF: 0.0119 AC: 633 AN: 53362

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00666 AC: 7402 AN: 1112008

Other (OTH) AF: 0.00667 AC: 403 AN: 60390

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152292 Hom.: 3 Cov.: 33 AF XY: 0.00436 AC XY: 325 AN XY: 74468

African (AFR) AF: 0.00106 AC: 44 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00691 AC: 470 AN: 68014

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00602 Hom.: 0

Bravo AF: 0.00384

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00569

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.5
DANN	Benign	0.62
PhyloP100		-2.5
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200816691; hg19: chr1-17332025; COSMIC: COSV100454265; COSMIC: COSV100454265;