rs538497077

chr1-17000309-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_022089.4(ATP13A2):c.844A>T(p.Ser282Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,582,072 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S282S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (4 hom.)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 2.57

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07707608).
• BP6: Variant 1-17000309-T-A is Benign according to our data. Variant chr1-17000309-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 533811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP13A2	NM_022089.4	c.844A>T	p.Ser282Cys	missense_variant	10/29	ENST00000326735.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP13A2	ENST00000326735.13	c.844A>T	p.Ser282Cys	missense_variant	10/29	1	NM_022089.4	A1
	ENST00000446261.1	n.188-4334T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151800 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000511 AC: 101 AN: 197728 Hom.: 1 AF XY: 0.000670 AC XY: 71 AN XY: 105968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000950

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000678

Gnomad SAS exome AF: 0.00254

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000782

GnomAD4 exome AF: 0.000215 AC: 308 AN: 1430154 Hom.: 4 Cov.: 35 AF XY: 0.000299 AC XY: 212 AN XY: 708522

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000838

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000210

Gnomad4 OTH exome AF: 0.000338

GnomAD4 genome AF: 0.000197 AC: 30 AN: 151918 Hom.: 1 Cov.: 31 AF XY: 0.000283 AC XY: 21 AN XY: 74274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000710 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000431 AC: 52

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;T;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.033	D;D;D;D;T
Sift4G	Benign	0.093	T;T;T;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.88
MutPred		0.74		Loss of disorder (P = 1e-04);.;.;.;.;
MVP		0.97
MPC		1.1
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.31
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs538497077; hg19: chr1-17326804;