NM_022089.4:c.705+228A>G

Variant names:

• chr1-17001806-T-C
• rs2871776
• NM_022089.4:c.705+228A>G

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.705+228A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 152,086 control chromosomes in the GnomAD database, including 24,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.56 (24940 hom., cov: 33)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.238
• Publications: 12 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: 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

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-17001806-T-C is Benign according to our data. Variant chr1-17001806-T-C is described in ClinVar as Benign. ClinVar VariationId is 703790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.705+228A>G		intron_variant	Intron 8 of 28	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.705+228A>G		intron_variant	Intron 8 of 28	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85241 AN: 151966 Hom.: 24879 Cov.: 33

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.538

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.561 AC: 85357 AN: 152086 Hom.: 24940 Cov.: 33 AF XY: 0.567 AC XY: 42187 AN XY: 74354

African (AFR) AF: 0.726 AC: 30136 AN: 41514

American (AMR) AF: 0.535 AC: 8169 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1778 AN: 3468

East Asian (EAS) AF: 0.715 AC: 3696 AN: 5170

South Asian (SAS) AF: 0.586 AC: 2820 AN: 4816

European-Finnish (FIN) AF: 0.524 AC: 5542 AN: 10574

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31484 AN: 67958

Other (OTH) AF: 0.544 AC: 1149 AN: 2112

Alfa AF: 0.593 Hom.: 7077

Bravo AF: 0.567

Asia WGS AF: 0.669 AC: 2325 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22285144) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.42
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs2871776; hg19: chr1-17328301; COSMIC: COSV58699256; COSMIC: COSV58699256;