1-17005410-G-A

Variant names:

• chr1-17005410-G-A
• rs554944790
• ENST00000617114.5:c.271C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_022089.4(ATP13A2):​c.252C>T​(p.His84His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000098 in 1,611,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.73
• Publications: 1 publications found

Genes affected

ENSG00000288636 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.069).
• BP6: Variant 1-17005410-G-A is Benign according to our data. Variant chr1-17005410-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 585469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.73 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.252C>T	p.His84His	synonymous	Exon 3 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.252C>T	p.His84His	synonymous	Exon 3 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.252C>T	p.His84His	synonymous	Exon 3 of 27	NP_001135446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288636	ENST00000617114.5	TSL:5	c.271C>T	p.Arg91Cys	missense	Exon 3 of 4	ENSP00000478781.2
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.252C>T	p.His84His	synonymous	Exon 3 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.252C>T	p.His84His	synonymous	Exon 3 of 29	ENSP00000413307.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 26 AN: 242738 AF XY: 0.0000833

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000973 AC: 142 AN: 1459486 Hom.: 0 Cov.: 32 AF XY: 0.0000882 AC XY: 64 AN XY: 725880

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.000249 AC: 11 AN: 44194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1110980

Other (OTH) AF: 0.000133 AC: 8 AN: 60296

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.000458 AC: 7 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000838 Hom.: 0

Bravo AF: 0.000227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ATP13A2-related disorder (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	-0.49
CADD	Uncertain	24
DANN	Benign	0.84
PhyloP100		2.7
PromoterAI		0.0046	Neutral
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: rs554944790; hg19: chr1-17331905;