1-16986896-G-C

Variant names:

• chr1-16986896-G-C
• rs56126202
• NM_022089.4:c.3144C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022089.4(ATP13A2):​c.3144C>G​(p.Thr1048Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,614,010 control chromosomes in the GnomAD database, including 554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1048T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (278 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (276 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -9.55
• Publications: 4 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-16986896-G-C is Benign according to our data. Variant chr1-16986896-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

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.3144C>G	p.Thr1048Thr	synonymous	Exon 27 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.3129C>G	p.Thr1043Thr	synonymous	Exon 27 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.3012C>G	p.Thr1004Thr	synonymous	Exon 26 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.3144C>G	p.Thr1048Thr	synonymous	Exon 27 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.3129C>G	p.Thr1043Thr	synonymous	Exon 27 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.3012C>G	p.Thr1004Thr	synonymous	Exon 26 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5345 AN: 152078 Hom.: 280 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.00922 AC: 2313 AN: 250794 AF XY: 0.00698

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00750

Gnomad ASJ exome AF: 0.00825

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000671

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00385 AC: 5632 AN: 1461816 Hom.: 276 Cov.: 70 AF XY: 0.00345 AC XY: 2510 AN XY: 727222

African (AFR) AF: 0.118 AC: 3955 AN: 33478

American (AMR) AF: 0.00852 AC: 381 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00830 AC: 217 AN: 26134

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

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5768

European-Non Finnish (NFE) AF: 0.000405 AC: 450 AN: 1111982

Other (OTH) AF: 0.00922 AC: 557 AN: 60392

GnomAD4 genome AF: 0.0352 AC: 5353 AN: 152194 Hom.: 278 Cov.: 32 AF XY: 0.0336 AC XY: 2501 AN XY: 74398

African (AFR) AF: 0.118 AC: 4900 AN: 41506

American (AMR) AF: 0.0210 AC: 322 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68006

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.00447 Hom.: 13

Bravo AF: 0.0401

Asia WGS AF: 0.00636 AC: 23 AN: 3476

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (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	-0.92
CADD	Benign	0.14
DANN	Benign	0.42
PhyloP100		-9.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs56126202; hg19: chr1-17313391;