NM_022089.4:c.3084-3C>T

Variant names:

• chr1-16986959-G-A
• rs7531163
• NM_022089.4:c.3084-3C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022089.4(ATP13A2):​c.3084-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,342 control chromosomes in the GnomAD database, including 53,206 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4955 hom., cov: 29)
  • Exomes 𝑓: 0.25 (48251 hom.)
• Consequence: ATP13A2 NM_022089.4 splice_region, intron
• Scores: Splicing: ADA: 0.001061
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.747
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-16986959-G-A is Benign according to our data. Variant chr1-16986959-G-A is described in ClinVar as Benign. ClinVar VariationId is 128471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

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.3084-3C>T		splice_region intron	N/A	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.3069-3C>T		splice_region intron	N/A	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.2952-3C>T		splice_region intron	N/A	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.3084-3C>T		splice_region intron	N/A	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.3069-3C>T		splice_region intron	N/A	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.2952-3C>T		splice_region intron	N/A	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36781 AN: 151530 Hom.: 4944 Cov.: 29

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.282 AC: 70700 AN: 250814 AF XY: 0.277

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.551

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.250 AC: 365088 AN: 1461694 Hom.: 48251 Cov.: 66 AF XY: 0.249 AC XY: 181231 AN XY: 727176

African (AFR) AF: 0.166 AC: 5556 AN: 33474

American (AMR) AF: 0.356 AC: 15899 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6866 AN: 26128

East Asian (EAS) AF: 0.534 AC: 21197 AN: 39694

South Asian (SAS) AF: 0.236 AC: 20318 AN: 86256

European-Finnish (FIN) AF: 0.310 AC: 16530 AN: 53366

Middle Eastern (MID) AF: 0.276 AC: 1591 AN: 5766

European-Non Finnish (NFE) AF: 0.235 AC: 261319 AN: 1111910

Other (OTH) AF: 0.262 AC: 15812 AN: 60390

GnomAD4 genome AF: 0.243 AC: 36817 AN: 151648 Hom.: 4955 Cov.: 29 AF XY: 0.251 AC XY: 18579 AN XY: 74050

African (AFR) AF: 0.166 AC: 6861 AN: 41388

American (AMR) AF: 0.338 AC: 5155 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 971 AN: 3468

East Asian (EAS) AF: 0.558 AC: 2829 AN: 5068

South Asian (SAS) AF: 0.244 AC: 1168 AN: 4786

European-Finnish (FIN) AF: 0.321 AC: 3371 AN: 10508

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15637 AN: 67878

Other (OTH) AF: 0.262 AC: 551 AN: 2104

Alfa AF: 0.235 Hom.: 2373

Bravo AF: 0.244

Asia WGS AF: 0.363 AC: 1262 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.249

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Kufor-Rakeb syndrome (3)
-	-	3	not provided (3)
-	-	1	Autosomal recessive spastic paraplegia type 78 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.0
DANN	Benign	0.71
PhyloP100		0.75
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.10
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: rs7531163; hg19: chr1-17313454; COSMIC: COSV104399909; COSMIC: COSV104399909;