rs542270701

Variant names:

• chr1-16986065-C-T
• rs542270701
• ENST00000341676.9:c.3397G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001141974.3(ATP13A2):​c.3397G>A​(p.Val1133Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,516,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V1133V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ATP13A2 NM_001141974.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.189
• Publications: 1 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: G2P, Illumina, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive spastic paraplegia type 78

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• parkinsonism due to ATP13A2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03981623).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141974.3. 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.*156G>A		3_prime_UTR	Exon 29 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141974.3		c.3397G>A	p.Val1133Ile	missense	Exon 27 of 27	NP_001135446.1	Q9NQ11-2
	ATP13A2	NM_001141973.3		c.*156G>A		3_prime_UTR	Exon 29 of 29	NP_001135445.1	Q9NQ11-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000341676.9	TSL:1	c.3397G>A	p.Val1133Ile	missense	Exon 27 of 27	ENSP00000341115.5	Q9NQ11-2
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.*156G>A		3_prime_UTR	Exon 29 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.*156G>A		3_prime_UTR	Exon 29 of 29	ENSP00000413307.1	Q9NQ11-3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000179 AC: 23 AN: 128784 AF XY: 0.000132

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000254

Gnomad OTH exome AF: 0.000568

GnomAD4 exome AF: 0.000200 AC: 273 AN: 1364038 Hom.: 0 Cov.: 30 AF XY: 0.000188 AC XY: 126 AN XY: 669808

African (AFR) AF: 0.000232 AC: 7 AN: 30130

American (AMR) AF: 0.000139 AC: 4 AN: 28722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22822

East Asian (EAS) AF: 0.00 AC: 0 AN: 35842

South Asian (SAS) AF: 0.00 AC: 0 AN: 74924

European-Finnish (FIN) AF: 0.000396 AC: 19 AN: 47968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.000223 AC: 237 AN: 1061790

Other (OTH) AF: 0.000106 AC: 6 AN: 56360

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74354

African (AFR) AF: 0.000361 AC: 15 AN: 41506

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.000105 AC: 11

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	4.4
DANN	Benign	0.94
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.34	T
PhyloP100		-0.19
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.25
Sift	Benign	0.24	T
Sift4G	Benign	0.42	T
Vest4		0.13
MVP		0.27
ClinPred		0.0051	T
GERP RS		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs542270701; hg19: chr1-17312560;