1-16986248-C-T

Variant names:

• chr1-16986248-C-T
• rs3170740
• ENST00000341676.9:c.3214G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001141974.3(ATP13A2):​c.3214G>A​(p.Ala1072Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 1,608,170 control chromosomes in the GnomAD database, including 201,659 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1072A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (14378 hom., cov: 32)
  • Exomes 𝑓: 0.50 (187281 hom.)
• Consequence: ATP13A2 NM_001141974.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -2.77
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.451812E-5).
• BP6: Variant 1-16986248-C-T is Benign according to our data. Variant chr1-16986248-C-T is described in ClinVar as Benign. ClinVar VariationId is 128475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141974.3. 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.3516G>A	p.Pro1172Pro	synonymous	Exon 29 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141974.3		c.3214G>A	p.Ala1072Thr	missense	Exon 27 of 27	NP_001135446.1	Q9NQ11-2
	ATP13A2	NM_001141973.3		c.3501G>A	p.Pro1167Pro	synonymous	Exon 29 of 29	NP_001135445.1	Q9NQ11-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000341676.9	TSL:1	c.3214G>A	p.Ala1072Thr	missense	Exon 27 of 27	ENSP00000341115.5	Q9NQ11-2
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.3516G>A	p.Pro1172Pro	synonymous	Exon 29 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.3501G>A	p.Pro1167Pro	synonymous	Exon 29 of 29	ENSP00000413307.1	Q9NQ11-3

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62322 AN: 151636 Hom.: 14373 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.424

GnomAD2 exomes AF: 0.470 AC: 110330 AN: 234588 AF XY: 0.476

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.295

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.502 AC: 731283 AN: 1456418 Hom.: 187281 Cov.: 77 AF XY: 0.502 AC XY: 363475 AN XY: 724118

African (AFR) AF: 0.182 AC: 6092 AN: 33424

American (AMR) AF: 0.478 AC: 20991 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 12286 AN: 25874

East Asian (EAS) AF: 0.304 AC: 12007 AN: 39438

South Asian (SAS) AF: 0.459 AC: 39262 AN: 85492

European-Finnish (FIN) AF: 0.488 AC: 25636 AN: 52546

Middle Eastern (MID) AF: 0.464 AC: 2607 AN: 5614

European-Non Finnish (NFE) AF: 0.526 AC: 584131 AN: 1110064

Other (OTH) AF: 0.471 AC: 28271 AN: 60082

GnomAD4 genome AF: 0.411 AC: 62332 AN: 151752 Hom.: 14378 Cov.: 32 AF XY: 0.407 AC XY: 30172 AN XY: 74178

African (AFR) AF: 0.198 AC: 8189 AN: 41300

American (AMR) AF: 0.446 AC: 6818 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1610 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1413 AN: 5130

South Asian (SAS) AF: 0.434 AC: 2094 AN: 4820

European-Finnish (FIN) AF: 0.475 AC: 5014 AN: 10562

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.527 AC: 35745 AN: 67884

Other (OTH) AF: 0.419 AC: 885 AN: 2110

Alfa AF: 0.488 Hom.: 20700

Bravo AF: 0.399

TwinsUK AF: 0.527 AC: 1955

ALSPAC AF: 0.523 AC: 2015

ESP6500AA AF: 0.217 AC: 944

ESP6500EA AF: 0.526 AC: 4491

ExAC AF: 0.455 AC: 54634

Asia WGS AF: 0.333 AC: 1158 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	3	Kufor-Rakeb syndrome (3)
-	-	1	Autosomal recessive spastic paraplegia type 78 (1)
-	-	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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	0.21
DANN	Benign	0.80
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.000045	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.8
PROVEAN	Benign	0.090	N
REVEL	Benign	0.24
Sift	Benign	0.99	T
Sift4G	Benign	0.60	T
Vest4		0.12
ClinPred		0.0029	T
GERP RS		-7.1
Mutation Taster		=97/3	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: rs3170740; hg19: chr1-17312743; COSMIC: COSV58697923; COSMIC: COSV58697923;