chr1-16993764-G-A

Variant names:

• chr1-16993764-G-A
• rs56351817
• NM_022089.4:c.1614C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022089.4(ATP13A2):​c.1614C>T​(p.Pro538Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,589,758 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (19 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.68
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-16993764-G-A is Benign according to our data. Variant chr1-16993764-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00343 (522/152326) while in subpopulation SAS AF = 0.0101 (49/4830). AF 95% confidence interval is 0.00788. There are 2 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1614C>T	p.Pro538Pro	synonymous	Exon 16 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.1599C>T	p.Pro533Pro	synonymous	Exon 16 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.1599C>T	p.Pro533Pro	synonymous	Exon 16 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.1614C>T	p.Pro538Pro	synonymous	Exon 16 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.1599C>T	p.Pro533Pro	synonymous	Exon 16 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.1599C>T	p.Pro533Pro	synonymous	Exon 16 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 521 AN: 152210 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00342 AC: 700 AN: 204484 AF XY: 0.00379

Gnomad AFR exome AF: 0.00623

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.00489

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00205 AC: 2947 AN: 1437432 Hom.: 19 Cov.: 31 AF XY: 0.00238 AC XY: 1698 AN XY: 713006

African (AFR) AF: 0.00630 AC: 208 AN: 32996

American (AMR) AF: 0.00531 AC: 220 AN: 41424

Ashkenazi Jewish (ASJ) AF: 0.00505 AC: 129 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 38366

South Asian (SAS) AF: 0.0102 AC: 842 AN: 82840

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50556

Middle Eastern (MID) AF: 0.0130 AC: 69 AN: 5328

European-Non Finnish (NFE) AF: 0.00116 AC: 1279 AN: 1100968

Other (OTH) AF: 0.00335 AC: 199 AN: 59396

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00352 AC XY: 262 AN XY: 74490

African (AFR) AF: 0.00604 AC: 251 AN: 41580

American (AMR) AF: 0.00490 AC: 75 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0101 AC: 49 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68022

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00246 Hom.: 1

Bravo AF: 0.00357

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Kufor-Rakeb syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	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	-0.78
CADD	Benign	0.96
DANN	Benign	0.91
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56351817; hg19: chr1-17320259;