rs200587951

Variant names:

• chr1-17005564-C-T
• rs200587951
• NM_022089.4:c.106-8G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000326735.13(ATP13A2):​c.106-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,614,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: ATP13A2 ENST00000326735.13 splice_region, intron
• Scores: Splicing: ADA: 0.00009074
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: -3.15
• 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: 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

ENSG00000288636 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-17005564-C-T is Benign according to our data. Variant chr1-17005564-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210379.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000326735.13. 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.106-8G>A		splice_region intron	N/A	NP_071372.1
	ATP13A2	NM_001141973.3		c.106-8G>A		splice_region intron	N/A	NP_001135445.1
	ATP13A2	NM_001141974.3		c.106-8G>A		splice_region intron	N/A	NP_001135446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.106-8G>A		splice_region intron	N/A	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.106-8G>A		splice_region intron	N/A	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.106-8G>A		splice_region intron	N/A	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000925 AC: 232 AN: 250896 AF XY: 0.000950

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000974 AC: 1424 AN: 1461864 Hom.: 1 Cov.: 33 AF XY: 0.000991 AC XY: 721 AN XY: 727230

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86250

European-Finnish (FIN) AF: 0.00182 AC: 97 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00112 AC: 1243 AN: 1112010

Other (OTH) AF: 0.000844 AC: 51 AN: 60396

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000686 AC XY: 51 AN XY: 74382

African (AFR) AF: 0.000217 AC: 9 AN: 41478

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68046

Other (OTH) AF: 0.00191 AC: 4 AN: 2094

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000563

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	Kufor-Rakeb syndrome (2)
-	-	1	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.88
PhyloP100		-3.1
PromoterAI		-0.023	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000091
dbscSNV1_RF	Benign	0.010
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: rs200587951; hg19: chr1-17332059;