rs115985012

Variant names:

• chr1-16986526-G-A
• rs115985012
• NM_022089.4:c.3342C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16986526-G-A
• chr1-16986526-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022089.4(ATP13A2):​c.3342C>T​(p.Thr1114Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,612,672 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (20 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.800
• Publications: 1 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=-0.71).
• BP6: Variant 1-16986526-G-A is Benign according to our data. Variant chr1-16986526-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 588527.
• BP7: Synonymous conserved (PhyloP=0.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00221 (337/152246) while in subpopulation NFE AF = 0.00407 (277/67996). AF 95% confidence interval is 0.00368. There are 0 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.3342C>T	p.Thr1114Thr	synonymous	Exon 28 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.3327C>T	p.Thr1109Thr	synonymous	Exon 28 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.3104-168C>T		intron	N/A	NP_001135446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.3342C>T	p.Thr1114Thr	synonymous	Exon 28 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.3327C>T	p.Thr1109Thr	synonymous	Exon 28 of 29	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.3104-168C>T		intron	N/A	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00231 AC: 567 AN: 245592 AF XY: 0.00245

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00110

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00351 AC: 5124 AN: 1460426 Hom.: 20 Cov.: 68 AF XY: 0.00341 AC XY: 2476 AN XY: 726548

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.000805 AC: 36 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86256

European-Finnish (FIN) AF: 0.00196 AC: 102 AN: 52136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00424 AC: 4711 AN: 1111886

Other (OTH) AF: 0.00356 AC: 215 AN: 60366

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00202 AC XY: 150 AN XY: 74424

African (AFR) AF: 0.000409 AC: 17 AN: 41548

American (AMR) AF: 0.00131 AC: 20 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00407 AC: 277 AN: 67996

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00222

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00409

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Kufor-Rakeb syndrome (1)
-	-	1	Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		0.80
Mutation Taster		=99/1	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: rs115985012; hg19: chr1-17313021; COSMIC: COSV58703596; COSMIC: COSV58703596;