1-16996954-T-C

Variant names:

• chr1-16996954-T-C
• rs9435736
• NM_022089.4:c.1195+66A>G

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.1195+66A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 1,566,436 control chromosomes in the GnomAD database, including 530,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49717 hom., cov: 32)
  • Exomes 𝑓: 0.82 (481197 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18
• Publications: 6 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=-0.99).
• BP6: Variant 1-16996954-T-C is Benign according to our data. Variant chr1-16996954-T-C is described in ClinVar as Benign. ClinVar VariationId is 1192485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A2	NM_022089.4	c.1195+66A>G		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.1195+66A>G		intron_variant	Intron 12 of 28	1	NM_022089.4	ENSP00000327214.8

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122642 AN: 152014 Hom.: 49690 Cov.: 32

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.818

Gnomad EAS AF: 0.846

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.821

GnomAD4 exome AF: 0.824 AC: 1165591 AN: 1414304 Hom.: 481197 AF XY: 0.822 AC XY: 575821 AN XY: 700902

African (AFR) AF: 0.747 AC: 24223 AN: 32416

American (AMR) AF: 0.884 AC: 33229 AN: 37590

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 20675 AN: 25438

East Asian (EAS) AF: 0.841 AC: 31335 AN: 37244

South Asian (SAS) AF: 0.749 AC: 61589 AN: 82272

European-Finnish (FIN) AF: 0.841 AC: 41080 AN: 48862

Middle Eastern (MID) AF: 0.818 AC: 3345 AN: 4088

European-Non Finnish (NFE) AF: 0.829 AC: 902202 AN: 1087858

Other (OTH) AF: 0.819 AC: 47913 AN: 58536

GnomAD4 genome AF: 0.807 AC: 122716 AN: 152132 Hom.: 49717 Cov.: 32 AF XY: 0.807 AC XY: 60039 AN XY: 74376

African (AFR) AF: 0.746 AC: 30954 AN: 41494

American (AMR) AF: 0.873 AC: 13349 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 2837 AN: 3468

East Asian (EAS) AF: 0.846 AC: 4348 AN: 5140

South Asian (SAS) AF: 0.737 AC: 3550 AN: 4820

European-Finnish (FIN) AF: 0.845 AC: 8967 AN: 10614

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 56029 AN: 67982

Other (OTH) AF: 0.813 AC: 1716 AN: 2112

Alfa AF: 0.770 Hom.: 3321

Bravo AF: 0.808

Asia WGS AF: 0.745 AC: 2590 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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 31, 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 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 93. 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.84
DANN	Benign	0.53
PhyloP100		-1.2
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: rs9435736; hg19: chr1-17323449;