1-16986063-A-G

Position:

• chr1-16986063-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000341676.9(ATP13A2):​c.3399T>C​(p.Val1133=) 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 1,514,874 control chromosomes in the GnomAD database, including 19 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. V1133V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (19 hom.)
• Consequence: ATP13A2 ENST00000341676.9 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.97

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-16986063-A-G is Benign according to our data. Variant chr1-16986063-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 293760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16986063-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00217 (329/151788) while in subpopulation NFE AF= 0.00399 (271/67922). AF 95% confidence interval is 0.0036. There are 0 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP13A2	NM_022089.4	c.*158T>C		3_prime_UTR_variant	29/29	ENST00000326735.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP13A2	ENST00000326735.13	c.*158T>C		3_prime_UTR_variant	29/29	1	NM_022089.4	A1
	ENST00000446261.1	n.187+6951A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 329 AN: 151668 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.00193 AC: 247 AN: 128086 Hom.: 1 AF XY: 0.00202 AC XY: 137 AN XY: 67696

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.000429

Gnomad ASJ exome AF: 0.000338

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000332

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00353 AC: 4811 AN: 1363086 Hom.: 19 Cov.: 30 AF XY: 0.00341 AC XY: 2284 AN XY: 669196

Gnomad4 AFR exome AF: 0.000432

Gnomad4 AMR exome AF: 0.000870

Gnomad4 ASJ exome AF: 0.000219

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000428

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00419

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00217 AC: 329 AN: 151788 Hom.: 0 Cov.: 31 AF XY: 0.00204 AC XY: 151 AN XY: 74152

Gnomad4 AFR AF: 0.000387

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00399

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00208 Hom.: 0

Bravo AF: 0.00217

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATP13A2: BP4, BP7 -

Kufor-Rakeb syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs185521359; hg19: chr1-17312558;