rs61734958

Variant names:

• chr1-16992042-A-G
• rs61734958
• NM_022089.4:c.2093T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022089.4(ATP13A2):​c.2093T>C​(p.Val698Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000823 in 1,613,402 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V698V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0470
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035814047).
• BP6: Variant 1-16992042-A-G is Benign according to our data. Variant chr1-16992042-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 533810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00455 (693/152368) while in subpopulation AFR AF = 0.0161 (670/41592). AF 95% confidence interval is 0.0151. There are 4 homozygotes in GnomAd4. There are 316 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.2093T>C	p.Val698Ala	missense	Exon 19 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.2078T>C	p.Val693Ala	missense	Exon 19 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.2078T>C	p.Val693Ala	missense	Exon 19 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.2093T>C	p.Val698Ala	missense	Exon 19 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.2078T>C	p.Val693Ala	missense	Exon 19 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.2078T>C	p.Val693Ala	missense	Exon 19 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.00452 AC: 688 AN: 152250 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00126 AC: 315 AN: 250532 AF XY: 0.000900

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000435 AC: 635 AN: 1461034 Hom.: 2 Cov.: 31 AF XY: 0.000389 AC XY: 283 AN XY: 726724

African (AFR) AF: 0.0156 AC: 522 AN: 33474

American (AMR) AF: 0.000783 AC: 35 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52946

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111714

Other (OTH) AF: 0.000961 AC: 58 AN: 60366

GnomAD4 genome AF: 0.00455 AC: 693 AN: 152368 Hom.: 4 Cov.: 33 AF XY: 0.00424 AC XY: 316 AN XY: 74514

African (AFR) AF: 0.0161 AC: 670 AN: 41592

American (AMR) AF: 0.000980 AC: 15 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00499

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.5
DANN	Benign	0.37
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N
PhyloP100		0.047
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.026
Sift	Benign	0.76	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.031
MVP		0.28
MPC		0.39
ClinPred		0.00079	T
GERP RS		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.020
gMVP		0.31
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: rs61734958; hg19: chr1-17318537;