1-16986788-C-T

Variant names:

• chr1-16986788-C-T
• rs56146840
• NM_022089.4:c.3235+17G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022089.4(ATP13A2):​c.3235+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,609,774 control chromosomes in the GnomAD database, including 598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (48 hom., cov: 33)
  • Exomes 𝑓: 0.025 (550 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.45
• Publications: 3 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=-0.8).
• BP6: Variant 1-16986788-C-T is Benign according to our data. Variant chr1-16986788-C-T is described in ClinVar as Benign. ClinVar VariationId is 261542.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 = 0.0239 (3637/152272) while in subpopulation NFE AF = 0.0263 (1789/68014). AF 95% confidence interval is 0.0253. There are 48 homozygotes in GnomAd4. There are 1781 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.3235+17G>A		intron	N/A	NP_071372.1
	ATP13A2	NM_001141973.3		c.3220+17G>A		intron	N/A	NP_001135445.1
	ATP13A2	NM_001141974.3		c.3103+17G>A		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.3235+17G>A		intron	N/A	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.3220+17G>A		intron	N/A	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.3103+17G>A		intron	N/A	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3638 AN: 152154 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0221 AC: 5304 AN: 240380 AF XY: 0.0225

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.0224

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0253 AC: 36917 AN: 1457502 Hom.: 550 Cov.: 63 AF XY: 0.0251 AC XY: 18220 AN XY: 724960

African (AFR) AF: 0.0240 AC: 803 AN: 33420

American (AMR) AF: 0.0229 AC: 1015 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 717 AN: 26048

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39544

South Asian (SAS) AF: 0.0175 AC: 1500 AN: 85836

European-Finnish (FIN) AF: 0.0220 AC: 1147 AN: 52174

Middle Eastern (MID) AF: 0.0469 AC: 249 AN: 5308

European-Non Finnish (NFE) AF: 0.0269 AC: 29861 AN: 1110694

Other (OTH) AF: 0.0270 AC: 1624 AN: 60160

GnomAD4 genome AF: 0.0239 AC: 3637 AN: 152272 Hom.: 48 Cov.: 33 AF XY: 0.0239 AC XY: 1781 AN XY: 74442

African (AFR) AF: 0.0214 AC: 889 AN: 41558

American (AMR) AF: 0.0258 AC: 394 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4832

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1789 AN: 68014

Other (OTH) AF: 0.0289 AC: 61 AN: 2114

Alfa AF: 0.0262 Hom.: 14

Bravo AF: 0.0240

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

May 01, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.80
CADD	Benign	9.1
DANN	Benign	0.69
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs56146840; hg19: chr1-17313283; COSMIC: COSV58701097; COSMIC: COSV58701097;