chr1-16996255-C-G

Variant names:

• chr1-16996255-C-G
• rs138546275
• NM_022089.4:c.1352G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022089.4(ATP13A2):​c.1352G>C​(p.Arg451Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R451Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP13A2 NM_022089.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003826
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.1352G>C	p.Arg451Pro	missense_variant, splice_region_variant	Exon 14 of 29	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.1352G>C	p.Arg451Pro	missense_variant, splice_region_variant	Exon 14 of 29	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	7.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;.;D;.;D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.
PhyloP100		-0.32
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.9	N;N;N;N;.;D
REVEL	Pathogenic	0.70
Sift	Benign	0.13	T;T;T;T;.;D
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.020	B;.;.;.;.;.
Vest4		0.52
MutPred		0.58		Loss of methylation at R451 (P = 0.0412);.;.;.;.;.;
MVP		0.70
MPC		1.0
ClinPred		0.79	D
GERP RS		-1.9
PromoterAI		-0.0036	Neutral
Varity_R		0.24
gMVP		0.84
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.086
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: rs138546275; hg19: chr1-17322750;