rs56290406

Variant names:

• chr1-17000045-G-A
• rs56290406
• NM_022089.4:c.1005C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022089.4(ATP13A2):​c.1005C>T​(p.Ala335Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,612,546 control chromosomes in the GnomAD database, including 1,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A335A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (144 hom., cov: 33)
  • Exomes 𝑓: 0.033 (959 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.46
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.05).
• BP6: Variant 1-17000045-G-A is Benign according to our data. Variant chr1-17000045-G-A is described in ClinVar as Benign. ClinVar VariationId is 128463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0624 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.1005C>T	p.Ala335Ala	synonymous	Exon 11 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.990C>T	p.Ala330Ala	synonymous	Exon 11 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.990C>T	p.Ala330Ala	synonymous	Exon 11 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.1005C>T	p.Ala335Ala	synonymous	Exon 11 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.990C>T	p.Ala330Ala	synonymous	Exon 11 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.990C>T	p.Ala330Ala	synonymous	Exon 11 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5914 AN: 152150 Hom.: 144 Cov.: 33

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0227

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0263 AC: 6501 AN: 246884 AF XY: 0.0256

Gnomad AFR exome AF: 0.0684

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0332 AC: 48442 AN: 1460278 Hom.: 959 Cov.: 32 AF XY: 0.0322 AC XY: 23387 AN XY: 726286

African (AFR) AF: 0.0709 AC: 2372 AN: 33468

American (AMR) AF: 0.0154 AC: 686 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0278 AC: 725 AN: 26088

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39678

South Asian (SAS) AF: 0.0155 AC: 1334 AN: 86124

European-Finnish (FIN) AF: 0.0229 AC: 1206 AN: 52742

Middle Eastern (MID) AF: 0.0175 AC: 101 AN: 5766

European-Non Finnish (NFE) AF: 0.0360 AC: 40050 AN: 1111434

Other (OTH) AF: 0.0326 AC: 1965 AN: 60312

GnomAD4 genome AF: 0.0389 AC: 5918 AN: 152268 Hom.: 144 Cov.: 33 AF XY: 0.0381 AC XY: 2836 AN XY: 74452

African (AFR) AF: 0.0644 AC: 2675 AN: 41540

American (AMR) AF: 0.0227 AC: 347 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4824

European-Finnish (FIN) AF: 0.0233 AC: 248 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2372 AN: 68016

Other (OTH) AF: 0.0393 AC: 83 AN: 2110

Alfa AF: 0.0340 Hom.: 177

Bravo AF: 0.0396

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0306

EpiControl AF: 0.0296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Kufor-Rakeb syndrome (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	-0.82
CADD	Benign	0.15
DANN	Benign	0.77
PhyloP100		-4.5
PromoterAI		-0.0096	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs56290406; hg19: chr1-17326540;