1-16996703-A-T

Variant names:

• chr1-16996703-A-T
• rs2076602
• NM_022089.4:c.1196-207T>A

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.1196-207T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 621,090 control chromosomes in the GnomAD database, including 18,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4007 hom., cov: 33)
  • Exomes 𝑓: 0.23 (14371 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.177
• Publications: 2 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=-0.9).
• BP6: Variant 1-16996703-A-T is Benign according to our data. Variant chr1-16996703-A-T is described in ClinVar as Benign. ClinVar VariationId is 1270970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.1196-207T>A		intron_variant	Intron 12 of 28	ENST00000326735.13	NP_071372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A2	ENST00000326735.13	c.1196-207T>A		intron_variant	Intron 12 of 28	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32139 AN: 152034 Hom.: 3997 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.229 AC: 107421 AN: 468936 Hom.: 14371 Cov.: 4 AF XY: 0.228 AC XY: 56646 AN XY: 248180

African (AFR) AF: 0.147 AC: 1885 AN: 12848

American (AMR) AF: 0.317 AC: 6398 AN: 20198

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 2458 AN: 14072

East Asian (EAS) AF: 0.533 AC: 16742 AN: 31388

South Asian (SAS) AF: 0.227 AC: 10556 AN: 46552

European-Finnish (FIN) AF: 0.289 AC: 9425 AN: 32622

Middle Eastern (MID) AF: 0.196 AC: 395 AN: 2014

European-Non Finnish (NFE) AF: 0.189 AC: 53474 AN: 282572

Other (OTH) AF: 0.228 AC: 6088 AN: 26670

GnomAD4 genome AF: 0.211 AC: 32171 AN: 152154 Hom.: 4007 Cov.: 33 AF XY: 0.222 AC XY: 16478 AN XY: 74372

African (AFR) AF: 0.146 AC: 6070 AN: 41504

American (AMR) AF: 0.305 AC: 4655 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3468

East Asian (EAS) AF: 0.564 AC: 2908 AN: 5156

South Asian (SAS) AF: 0.239 AC: 1155 AN: 4826

European-Finnish (FIN) AF: 0.310 AC: 3284 AN: 10594

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12758 AN: 68000

Other (OTH) AF: 0.228 AC: 483 AN: 2114

Alfa AF: 0.186 Hom.: 343

Bravo AF: 0.211

Asia WGS AF: 0.363 AC: 1259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.1
DANN	Benign	0.82
PhyloP100		0.18
PromoterAI		-0.0086	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: rs2076602; hg19: chr1-17323198;