rs148970081

Variant names:

• chr1-16997087-G-A
• rs148970081
• NM_022089.4:c.1128C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_022089.4(ATP13A2):​c.1128C>T​(p.Cys376Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,613,486 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.74
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-16997087-G-A is Benign according to our data. Variant chr1-16997087-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293799.
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.

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.1128C>T	p.Cys376Cys	synonymous	Exon 12 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.1113C>T	p.Cys371Cys	synonymous	Exon 12 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.1113C>T	p.Cys371Cys	synonymous	Exon 12 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.1128C>T	p.Cys376Cys	synonymous	Exon 12 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.1113C>T	p.Cys371Cys	synonymous	Exon 12 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.1113C>T	p.Cys371Cys	synonymous	Exon 12 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000495 AC: 124 AN: 250646 AF XY: 0.000479

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000259 AC: 378 AN: 1461312 Hom.: 1 Cov.: 33 AF XY: 0.000289 AC XY: 210 AN XY: 726990

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 287 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111982

Other (OTH) AF: 0.000779 AC: 47 AN: 60362

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000883 Hom.: 0

Bravo AF: 0.000389

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	Kufor-Rakeb syndrome (1)
-	-	1	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.8
DANN	Benign	0.85
PhyloP100		-1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs148970081; hg19: chr1-17323582; COSMIC: COSV100454068; COSMIC: COSV100454068;