1-17004716-G-C

Variant names:

• chr1-17004716-G-C
• rs55979991
• NM_022089.4:c.453C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022089.4(ATP13A2):​c.453C>G​(p.Ser151Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S151S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP13A2 NM_022089.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.730
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041392624).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.453C>G	p.Ser151Arg	missense	Exon 5 of 29	NP_071372.1
	ATP13A2	NM_001141973.3		c.453C>G	p.Ser151Arg	missense	Exon 5 of 29	NP_001135445.1
	ATP13A2	NM_001141974.3		c.453C>G	p.Ser151Arg	missense	Exon 5 of 27	NP_001135446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.453C>G	p.Ser151Arg	missense	Exon 5 of 29	ENSP00000327214.8
	ATP13A2	ENST00000452699.5	TSL:1	c.453C>G	p.Ser151Arg	missense	Exon 5 of 29	ENSP00000413307.1
	ATP13A2	ENST00000341676.9	TSL:1	c.453C>G	p.Ser151Arg	missense	Exon 5 of 27	ENSP00000341115.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.28
DANN	Benign	0.88
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.73
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.027
Sift	Benign	0.46	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
Vest4		0.082
MutPred		0.30		Gain of MoRF binding (P = 0.0294)
MVP		0.33
MPC		0.36
ClinPred		0.080	T
GERP RS		-2.3
PromoterAI		0.031	Neutral
Varity_R		0.029
gMVP		0.27
Mutation Taster		=98/2	polymorphism

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: rs55979991; hg19: chr1-17331211;