rs528943677

Variant names:

• chr1-16986355-C-A
• rs528943677
• NM_022089.4:c.3409G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16986355-C-A
• chr1-16986355-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022089.4(ATP13A2):​c.3409G>T​(p.Val1137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1137M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• Publications: 0 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: 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

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04996717).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.3409G>T	p.Val1137Leu	missense	Exon 29 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.3394G>T	p.Val1132Leu	missense	Exon 29 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.3107G>T	p.Arg1036Leu	missense	Exon 27 of 27	NP_001135446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.3409G>T	p.Val1137Leu	missense	Exon 29 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.3394G>T	p.Val1132Leu	missense	Exon 29 of 29	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.3107G>T	p.Arg1036Leu	missense	Exon 27 of 27	ENSP00000341115.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427330 Hom.: 0 Cov.: 68 AF XY: 0.00 AC XY: 0 AN XY: 707786

African (AFR) AF: 0.00 AC: 0 AN: 32832

American (AMR) AF: 0.00 AC: 0 AN: 38904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 37920

South Asian (SAS) AF: 0.00 AC: 0 AN: 82950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097318

Other (OTH) AF: 0.00 AC: 0 AN: 59246

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.0034	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.055
DANN	Benign	0.97
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.84	T
PhyloP100		0.13
PROVEAN	Benign	2.9	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Uncertain	0.054	T
Vest4		0.17
MutPred		0.34		Loss of solvent accessibility (P = 0.0079)
MVP		0.22
ClinPred		0.053	T
GERP RS		-0.90
Varity_R		0.045
Mutation Taster		=96/4	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: rs528943677; hg19: chr1-17312850;