NM_022089.4:c.3236-34G>A

Variant names:

• chr1-16986666-C-T
• rs149826987
• NM_022089.4:c.3236-34G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022089.4(ATP13A2):​c.3236-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,582,480 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (8 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.37
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-16986666-C-T is Benign according to our data. Variant chr1-16986666-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 434437.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00262 (398/152198) while in subpopulation AMR AF = 0.00464 (71/15296). AF 95% confidence interval is 0.00377. There are 1 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.3236-34G>A		intron_variant	Intron 27 of 28	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.3236-34G>A		intron_variant	Intron 27 of 28	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00306 AC: 609 AN: 199106 AF XY: 0.00308

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00193

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00394 AC: 5635 AN: 1430282 Hom.: 8 Cov.: 37 AF XY: 0.00386 AC XY: 2744 AN XY: 710070

African (AFR) AF: 0.000731 AC: 24 AN: 32810

American (AMR) AF: 0.00290 AC: 117 AN: 40276

Ashkenazi Jewish (ASJ) AF: 0.000351 AC: 9 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 38244

South Asian (SAS) AF: 0.000572 AC: 48 AN: 83956

European-Finnish (FIN) AF: 0.00141 AC: 63 AN: 44636

Middle Eastern (MID) AF: 0.000855 AC: 4 AN: 4678

European-Non Finnish (NFE) AF: 0.00466 AC: 5131 AN: 1100732

Other (OTH) AF: 0.00403 AC: 239 AN: 59312

GnomAD4 genome AF: 0.00262 AC: 398 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74406

African (AFR) AF: 0.000819 AC: 34 AN: 41532

American (AMR) AF: 0.00464 AC: 71 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00390 AC: 265 AN: 67986

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00362 Hom.: 0

Bravo AF: 0.00294

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.71
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs149826987; hg19: chr1-17313161;