chr1-17004983-C-T

Variant names:

• chr1-17004983-C-T
• rs41273157
• NM_022089.4:c.347+31G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022089.4(ATP13A2):​c.347+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,288 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.020 (351 hom.)
• Consequence: ATP13A2 NM_022089.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-17004983-C-T is Benign according to our data. Variant chr1-17004983-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1212215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1926/152228) while in subpopulation NFE AF = 0.0208 (1411/67982). AF 95% confidence interval is 0.0199. There are 22 homozygotes in GnomAd4. There are 915 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.347+31G>A		intron	N/A	NP_071372.1
	ATP13A2	NM_001141973.3		c.347+31G>A		intron	N/A	NP_001135445.1
	ATP13A2	NM_001141974.3		c.347+31G>A		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.347+31G>A		intron	N/A	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.347+31G>A		intron	N/A	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.347+31G>A		intron	N/A	ENSP00000341115.5

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1927 AN: 152110 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.0149 AC: 3729 AN: 250342 AF XY: 0.0162

Gnomad AFR exome AF: 0.00328

Gnomad AMR exome AF: 0.00617

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0211

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0198 AC: 28868 AN: 1461060 Hom.: 351 Cov.: 33 AF XY: 0.0199 AC XY: 14497 AN XY: 726798

African (AFR) AF: 0.00284 AC: 95 AN: 33462

American (AMR) AF: 0.00640 AC: 286 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0231 AC: 1988 AN: 86214

European-Finnish (FIN) AF: 0.0112 AC: 597 AN: 53282

Middle Eastern (MID) AF: 0.0198 AC: 105 AN: 5312

European-Non Finnish (NFE) AF: 0.0222 AC: 24693 AN: 1111934

Other (OTH) AF: 0.0172 AC: 1035 AN: 60312

GnomAD4 genome AF: 0.0127 AC: 1926 AN: 152228 Hom.: 22 Cov.: 32 AF XY: 0.0123 AC XY: 915 AN XY: 74430

African (AFR) AF: 0.00318 AC: 132 AN: 41558

American (AMR) AF: 0.00870 AC: 133 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4822

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0208 AC: 1411 AN: 67982

Other (OTH) AF: 0.00997 AC: 21 AN: 2106

Alfa AF: 0.0115 Hom.: 2

Bravo AF: 0.0120

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		1.1
PromoterAI		-0.041	Neutral
Mutation Taster		=100/0	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: rs41273157; hg19: chr1-17331478;