chr1-16985978-T-G

Variant names:

• chr1-16985978-T-G
• rs777596557
• NM_022089.4:c.*243A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_022089.4(ATP13A2):​c.*243A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,442,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ATP13A2 NM_022089.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34
• 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: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Illumina
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000243 (314/1290236) while in subpopulation MID AF = 0.00423 (22/5204). AF 95% confidence interval is 0.00286. There are 0 homozygotes in GnomAdExome4. There are 155 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.*243A>C		3_prime_UTR	Exon 29 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.*243A>C		3_prime_UTR	Exon 29 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.*7A>C		3_prime_UTR	Exon 27 of 27	NP_001135446.1	Q9NQ11-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.*243A>C		3_prime_UTR	Exon 29 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.*243A>C		3_prime_UTR	Exon 29 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.*7A>C		3_prime_UTR	Exon 27 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 151830 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000271 AC: 19 AN: 70132 AF XY: 0.000264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00495

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000295

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000243 AC: 314 AN: 1290236 Hom.: 0 Cov.: 30 AF XY: 0.000248 AC XY: 155 AN XY: 623896

African (AFR) AF: 0.000179 AC: 5 AN: 27950

American (AMR) AF: 0.000219 AC: 4 AN: 18260

Ashkenazi Jewish (ASJ) AF: 0.00443 AC: 83 AN: 18744

East Asian (EAS) AF: 0.00 AC: 0 AN: 34070

South Asian (SAS) AF: 0.000165 AC: 10 AN: 60562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44048

Middle Eastern (MID) AF: 0.00423 AC: 22 AN: 5204

European-Non Finnish (NFE) AF: 0.000147 AC: 151 AN: 1028210

Other (OTH) AF: 0.000733 AC: 39 AN: 53188

GnomAD4 genome AF: 0.000283 AC: 43 AN: 151830 Hom.: 0 Cov.: 31 AF XY: 0.000297 AC XY: 22 AN XY: 74164

African (AFR) AF: 0.0000242 AC: 1 AN: 41322

American (AMR) AF: 0.000197 AC: 3 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67934

Other (OTH) AF: 0.00144 AC: 3 AN: 2088

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Kufor-Rakeb syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		2.3
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: rs777596557; hg19: chr1-17312473;