rs761421

Variant names:

• chr1-16987159-C-T
• rs761421
• NM_022089.4:c.2970G>A

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.2970G>A​(p.Val990Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,612,896 control chromosomes in the GnomAD database, including 203,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14650 hom., cov: 33)
  • Exomes 𝑓: 0.50 (188913 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.854
• Publications: 24 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: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Illumina
• 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=-0.61).
• BP6: Variant 1-16987159-C-T is Benign according to our data. Variant chr1-16987159-C-T is described in ClinVar as Benign. ClinVar VariationId is 128470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.854 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 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.2970G>A	p.Val990Val	synonymous	Exon 26 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.2955G>A	p.Val985Val	synonymous	Exon 26 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.2838G>A	p.Val946Val	synonymous	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.2970G>A	p.Val990Val	synonymous	Exon 26 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.2955G>A	p.Val985Val	synonymous	Exon 26 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.2838G>A	p.Val946Val	synonymous	Exon 25 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63475 AN: 151926 Hom.: 14645 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.465 AC: 115513 AN: 248224 AF XY: 0.471

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.283

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.504 AC: 735772 AN: 1460852 Hom.: 188913 Cov.: 79 AF XY: 0.504 AC XY: 365963 AN XY: 726744

African (AFR) AF: 0.205 AC: 6869 AN: 33466

American (AMR) AF: 0.475 AC: 21220 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 12648 AN: 26102

East Asian (EAS) AF: 0.305 AC: 12084 AN: 39682

South Asian (SAS) AF: 0.472 AC: 40712 AN: 86236

European-Finnish (FIN) AF: 0.485 AC: 25695 AN: 52970

Middle Eastern (MID) AF: 0.474 AC: 2700 AN: 5700

European-Non Finnish (NFE) AF: 0.526 AC: 585279 AN: 1111694

Other (OTH) AF: 0.473 AC: 28565 AN: 60346

GnomAD4 genome AF: 0.418 AC: 63492 AN: 152044 Hom.: 14650 Cov.: 33 AF XY: 0.413 AC XY: 30710 AN XY: 74276

African (AFR) AF: 0.220 AC: 9142 AN: 41492

American (AMR) AF: 0.447 AC: 6840 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1643 AN: 3472

East Asian (EAS) AF: 0.274 AC: 1413 AN: 5160

South Asian (SAS) AF: 0.453 AC: 2186 AN: 4822

European-Finnish (FIN) AF: 0.474 AC: 5005 AN: 10568

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35808 AN: 67928

Other (OTH) AF: 0.426 AC: 900 AN: 2114

Alfa AF: 0.491 Hom.: 11599

Bravo AF: 0.407

Asia WGS AF: 0.339 AC: 1178 AN: 3478

EpiCase AF: 0.516

EpiControl AF: 0.518

ClinVar

ClinVar submissions

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	-0.61
CADD	Benign	0.12
DANN	Benign	0.90
PhyloP100		-0.85
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: rs761421; hg19: chr1-17313654; COSMIC: COSV58699127; COSMIC: COSV58699127;