NM_022089.4:c.289-109T>C

Variant names:

• chr1-17005181-A-G
• rs3738814
• NM_022089.4:c.289-109T>C

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.289-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,514,810 control chromosomes in the GnomAD database, including 166,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21091 hom., cov: 32)
  • Exomes 𝑓: 0.46 (145383 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0320
• Publications: 47 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

ENSG00000288636 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-17005181-A-G is Benign according to our data. Variant chr1-17005181-A-G is described in ClinVar as Benign. ClinVar VariationId is 1270274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.289-109T>C		intron_variant	Intron 3 of 28	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.289-109T>C		intron_variant	Intron 3 of 28	1	NM_022089.4	ENSP00000327214.8
ENSG00000288636	ENST00000617114.5	c.308-109T>C		intron_variant	Intron 3 of 3	5		ENSP00000478781.2

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78651 AN: 151868 Hom.: 21041 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.457 AC: 622609 AN: 1362826 Hom.: 145383 Cov.: 22 AF XY: 0.459 AC XY: 313272 AN XY: 681916

African (AFR) AF: 0.653 AC: 20359 AN: 31158

American (AMR) AF: 0.497 AC: 21139 AN: 42522

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 11820 AN: 25330

East Asian (EAS) AF: 0.682 AC: 26204 AN: 38410

South Asian (SAS) AF: 0.557 AC: 46233 AN: 83058

European-Finnish (FIN) AF: 0.492 AC: 25472 AN: 51810

Middle Eastern (MID) AF: 0.502 AC: 2768 AN: 5516

European-Non Finnish (NFE) AF: 0.429 AC: 440966 AN: 1028008

Other (OTH) AF: 0.485 AC: 27648 AN: 57014

GnomAD4 genome AF: 0.518 AC: 78756 AN: 151984 Hom.: 21091 Cov.: 32 AF XY: 0.525 AC XY: 39035 AN XY: 74282

African (AFR) AF: 0.646 AC: 26774 AN: 41474

American (AMR) AF: 0.512 AC: 7812 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1666 AN: 3464

East Asian (EAS) AF: 0.715 AC: 3675 AN: 5140

South Asian (SAS) AF: 0.579 AC: 2793 AN: 4826

European-Finnish (FIN) AF: 0.501 AC: 5287 AN: 10560

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.428 AC: 29110 AN: 67936

Other (OTH) AF: 0.507 AC: 1069 AN: 2110

Alfa AF: 0.465 Hom.: 78838

Bravo AF: 0.523

Asia WGS AF: 0.658 AC: 2286 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 71% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 66. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.43
PhyloP100		-0.032
PromoterAI		-0.032	Neutral
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: rs3738814; hg19: chr1-17331676; COSMIC: COSV58699306; COSMIC: COSV58699306;