rs117758987

Variant names:

• chr1-16997011-G-A
• rs117758987
• NM_022089.4:c.1195+9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022089.4(ATP13A2):​c.1195+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,610,980 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (36 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.176
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-16997011-G-A is Benign according to our data. Variant chr1-16997011-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 293797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00264 (402/152286) while in subpopulation EAS AF = 0.04 (207/5174). AF 95% confidence interval is 0.0355. There are 6 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1195+9C>T		intron	N/A	NP_071372.1
	ATP13A2	NM_001141973.3		c.1180+9C>T		intron	N/A	NP_001135445.1
	ATP13A2	NM_001141974.3		c.1180+9C>T		intron	N/A	NP_001135446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.1195+9C>T		intron	N/A	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.1180+9C>T		intron	N/A	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.1180+9C>T		intron	N/A	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152168 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00453 AC: 1115 AN: 246302 AF XY: 0.00431

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0446

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00161 AC: 2348 AN: 1458694 Hom.: 36 Cov.: 33 AF XY: 0.00160 AC XY: 1162 AN XY: 725606

African (AFR) AF: 0.0000299 AC: 1 AN: 33396

American (AMR) AF: 0.000247 AC: 11 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0394 AC: 1565 AN: 39672

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86062

European-Finnish (FIN) AF: 0.00979 AC: 517 AN: 52810

Middle Eastern (MID) AF: 0.000692 AC: 3 AN: 4336

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111580

Other (OTH) AF: 0.00176 AC: 106 AN: 60176

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152286 Hom.: 6 Cov.: 31 AF XY: 0.00377 AC XY: 281 AN XY: 74444

African (AFR) AF: 0.0000722 AC: 3 AN: 41560

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0400 AC: 207 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000310 Hom.: 0

Bravo AF: 0.00206

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (2)
-	-	2	not provided (2)
-	-	1	ATP13A2-related disorder (1)
-	-	1	Kufor-Rakeb syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.2
DANN	Benign	0.49
PhyloP100		0.18
Mutation Taster		=100/0	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: rs117758987; hg19: chr1-17323506; COSMIC: COSV58702436; COSMIC: COSV58702436;