NM_022089.4:c.3236-30C>T

Variant names:

• chr1-16986662-G-A
• rs2076605
• NM_022089.4:c.3236-30C>T

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.3236-30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,587,734 control chromosomes in the GnomAD database, including 200,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14622 hom., cov: 30)
  • Exomes 𝑓: 0.50 (186033 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.13
• Publications: 10 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=-0.89).
• BP6: Variant 1-16986662-G-A is Benign according to our data. Variant chr1-16986662-G-A is described in ClinVar as Benign. ClinVar VariationId is 559000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.3236-30C>T		intron	N/A	NP_071372.1
	ATP13A2	NM_001141973.3		c.3221-30C>T		intron	N/A	NP_001135445.1
	ATP13A2	NM_001141974.3		c.3103+143C>T		intron	N/A	NP_001135446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.3236-30C>T		intron	N/A	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.3221-30C>T		intron	N/A	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.3103+143C>T		intron	N/A	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63323 AN: 151670 Hom.: 14617 Cov.: 30

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.471 AC: 98011 AN: 208288 AF XY: 0.476

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.484

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.476

GnomAD4 exome AF: 0.504 AC: 724300 AN: 1435946 Hom.: 186033 Cov.: 48 AF XY: 0.504 AC XY: 359756 AN XY: 713304

African (AFR) AF: 0.202 AC: 6657 AN: 32984

American (AMR) AF: 0.477 AC: 19608 AN: 41124

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 12460 AN: 25730

East Asian (EAS) AF: 0.308 AC: 11893 AN: 38640

South Asian (SAS) AF: 0.473 AC: 39972 AN: 84570

European-Finnish (FIN) AF: 0.486 AC: 22157 AN: 45588

Middle Eastern (MID) AF: 0.492 AC: 2392 AN: 4864

European-Non Finnish (NFE) AF: 0.527 AC: 580996 AN: 1102988

Other (OTH) AF: 0.474 AC: 28165 AN: 59458

GnomAD4 genome AF: 0.417 AC: 63340 AN: 151788 Hom.: 14622 Cov.: 30 AF XY: 0.413 AC XY: 30628 AN XY: 74170

African (AFR) AF: 0.218 AC: 9049 AN: 41420

American (AMR) AF: 0.447 AC: 6822 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1639 AN: 3468

East Asian (EAS) AF: 0.281 AC: 1436 AN: 5118

South Asian (SAS) AF: 0.453 AC: 2184 AN: 4818

European-Finnish (FIN) AF: 0.473 AC: 4993 AN: 10552

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35759 AN: 67842

Other (OTH) AF: 0.426 AC: 897 AN: 2106

Alfa AF: 0.416 Hom.: 6374

Bravo AF: 0.407

Asia WGS AF: 0.342 AC: 1190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 69% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 64. Only high quality variants are reported.

Autosomal recessive spastic paraplegia type 78 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Kufor-Rakeb syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2076605; hg19: chr1-17313157; COSMIC: COSV58702203; COSMIC: COSV58702203;