1-16986248-C-G

Variant names:

• chr1-16986248-C-G
• rs3170740
• ENST00000341676.9:c.3214G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001141974.3(ATP13A2):​c.3214G>C​(p.Ala1072Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 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. A1072T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP13A2 NM_001141974.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.77
• Publications: 41 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10876191).

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.3516G>C	p.Pro1172Pro	synonymous	Exon 29 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141974.3		c.3214G>C	p.Ala1072Pro	missense	Exon 27 of 27	NP_001135446.1	Q9NQ11-2
	ATP13A2	NM_001141973.3		c.3501G>C	p.Pro1167Pro	synonymous	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.3214G>C	p.Ala1072Pro	missense	Exon 27 of 27	ENSP00000341115.5	Q9NQ11-2
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.3516G>C	p.Pro1172Pro	synonymous	Exon 29 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.3501G>C	p.Pro1167Pro	synonymous	Exon 29 of 29	ENSP00000413307.1	Q9NQ11-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 77

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	0.11
DANN	Benign	0.90
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.55	T
PhyloP100		-2.8
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.21
Sift	Benign	0.23	T
Sift4G	Benign	0.40	T
Vest4		0.27
MutPred		0.31		Gain of glycosylation at A1072 (P = 0.0231)
MVP		0.24
ClinPred		0.077	T
GERP RS		-7.1
Mutation Taster		=98/2	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: rs3170740; hg19: chr1-17312743;