1-16988207-C-T

Variant names:

• chr1-16988207-C-T
• rs3738815
• NM_022089.4:c.2790G>A

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.2790G>A​(p.Ser930Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,613,830 control chromosomes in the GnomAD database, including 39,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S930S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (4003 hom., cov: 33)
  • Exomes 𝑓: 0.21 (35051 hom.)
• Consequence: ATP13A2 NM_022089.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.31
• Publications: 38 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=-0.61).
• BP6: Variant 1-16988207-C-T is Benign according to our data. Variant chr1-16988207-C-T is described in ClinVar as Benign. ClinVar VariationId is 128468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 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.2790G>A	p.Ser930Ser	synonymous	Exon 25 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141973.3		c.2775G>A	p.Ser925Ser	synonymous	Exon 25 of 29	NP_001135445.1	Q9NQ11-3
	ATP13A2	NM_001141974.3		c.2658G>A	p.Ser886Ser	synonymous	Exon 24 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.2790G>A	p.Ser930Ser	synonymous	Exon 25 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.2775G>A	p.Ser925Ser	synonymous	Exon 25 of 29	ENSP00000413307.1	Q9NQ11-3
	ATP13A2	ENST00000341676.9	TSL:1	c.2658G>A	p.Ser886Ser	synonymous	Exon 24 of 27	ENSP00000341115.5	Q9NQ11-2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32184 AN: 152022 Hom.: 3993 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.249 AC: 62714 AN: 251422 AF XY: 0.245

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.551

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.208 AC: 304210 AN: 1461690 Hom.: 35051 Cov.: 36 AF XY: 0.208 AC XY: 151555 AN XY: 727150

African (AFR) AF: 0.148 AC: 4939 AN: 33476

American (AMR) AF: 0.330 AC: 14739 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4603 AN: 26136

East Asian (EAS) AF: 0.534 AC: 21186 AN: 39698

South Asian (SAS) AF: 0.227 AC: 19549 AN: 86256

European-Finnish (FIN) AF: 0.293 AC: 15641 AN: 53408

Middle Eastern (MID) AF: 0.208 AC: 1199 AN: 5768

European-Non Finnish (NFE) AF: 0.188 AC: 209077 AN: 1111848

Other (OTH) AF: 0.220 AC: 13277 AN: 60386

GnomAD4 genome AF: 0.212 AC: 32216 AN: 152140 Hom.: 4003 Cov.: 33 AF XY: 0.222 AC XY: 16509 AN XY: 74362

African (AFR) AF: 0.148 AC: 6128 AN: 41520

American (AMR) AF: 0.305 AC: 4669 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2888 AN: 5152

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

European-Finnish (FIN) AF: 0.311 AC: 3282 AN: 10564

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

European-Non Finnish (NFE) AF: 0.188 AC: 12754 AN: 67992

Other (OTH) AF: 0.228 AC: 481 AN: 2114

Alfa AF: 0.196 Hom.: 6125

Bravo AF: 0.211

Asia WGS AF: 0.358 AC: 1242 AN: 3478

EpiCase AF: 0.197

EpiControl AF: 0.200

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Kufor-Rakeb syndrome (2)
-	-	1	Inborn genetic diseases (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	-0.61
CADD	Benign	0.85
DANN	Benign	0.89
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3738815; hg19: chr1-17314702; COSMIC: COSV58700021; COSMIC: COSV58700021;