chr1-17000272-C-T

Variant names:

• chr1-17000272-C-T
• rs56367069
• NM_022089.4:c.881G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022089.4(ATP13A2):​c.881G>A​(p.Arg294Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,577,728 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 31)
  • Exomes 𝑓: 0.015 (198 hom.)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: -0.400
• Publications: 15 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 -16 ACMG points.

• BP6: Variant 1-17000272-C-T is Benign according to our data. Variant chr1-17000272-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1789/151912) while in subpopulation NFE AF = 0.0163 (1108/67922). AF 95% confidence interval is 0.0155. There are 22 homozygotes in GnomAd4. There are 857 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.881G>A	p.Arg294Gln	missense	Exon 10 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.866G>A	p.Arg289Gln	missense	Exon 10 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.866G>A	p.Arg289Gln	missense	Exon 10 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.881G>A	p.Arg294Gln	missense	Exon 10 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.866G>A	p.Arg289Gln	missense	Exon 10 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.866G>A	p.Arg289Gln	missense	Exon 10 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1790 AN: 151794 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0178

GnomAD2 exomes AF: 0.0117 AC: 2284 AN: 195112 AF XY: 0.0118

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0381

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0152 AC: 21696 AN: 1425816 Hom.: 198 Cov.: 38 AF XY: 0.0150 AC XY: 10587 AN XY: 705760

African (AFR) AF: 0.00241 AC: 79 AN: 32834

American (AMR) AF: 0.0126 AC: 491 AN: 39122

Ashkenazi Jewish (ASJ) AF: 0.0387 AC: 983 AN: 25398

East Asian (EAS) AF: 0.000158 AC: 6 AN: 37900

South Asian (SAS) AF: 0.00412 AC: 336 AN: 81644

European-Finnish (FIN) AF: 0.0110 AC: 559 AN: 50600

Middle Eastern (MID) AF: 0.00819 AC: 47 AN: 5740

European-Non Finnish (NFE) AF: 0.0166 AC: 18192 AN: 1093612

Other (OTH) AF: 0.0170 AC: 1003 AN: 58966

GnomAD4 genome AF: 0.0118 AC: 1789 AN: 151912 Hom.: 22 Cov.: 31 AF XY: 0.0115 AC XY: 857 AN XY: 74228

African (AFR) AF: 0.00282 AC: 117 AN: 41434

American (AMR) AF: 0.0152 AC: 232 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3466

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5122

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4808

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1108 AN: 67922

Other (OTH) AF: 0.0176 AC: 37 AN: 2104

Alfa AF: 0.0142 Hom.: 66

Bravo AF: 0.0113

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.00812 AC: 975

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	5	not specified (5)
-	-	1	Inborn genetic diseases (1)
-	-	1	Kufor-Rakeb syndrome (1)
-	-	1	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.40
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.12
Sift	Benign	0.16	T
Sift4G	Benign	0.48	T
Polyphen		0.080	B
Vest4		0.25
MPC		0.37
ClinPred		0.0042	T
GERP RS		-0.71
PromoterAI		-0.083	Neutral
Varity_R		0.026
gMVP		0.31
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56367069; hg19: chr1-17326767; COSMIC: COSV58700715; COSMIC: COSV58700715;