Genetic Variant ATP8A2:p.Asn3Lys (chr13-25372221-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016529.6(ATP8A2):c.9C>A(p.Asn3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATP8A2
NM_016529.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

Publications

0 publications found

Variant links:

Genes affected

ATP8A2 (HGNC:13533): (ATPase phospholipid transporting 8A2) The protein encoded by this gene is a member of the P4 ATPase family of proteins, which are thought to be involved in a process called lipid flipping, whereby phospholipids are translocated inwards from the exoplasmic leaflet to the cytosolic leaflet of the cell membrane, which aids in generating and maintaining asymmetry in membrane lipids. This protein is predicted to contain an E1 E2 ATPase, a haloacid dehalogenase-like hydrolase (HAD) domain, and multiple transmembrane domains. Associations between this protein and cell cycle control protein 50A are important for translocation of phosphatidylserine across membranes. Mutations in this gene have been associated with a syndrome (CAMRQ4) characterized by cerebellar ataxia and cognitive disabilities. In addition, a translocation breakpoint within this gene was observed in an individual with neurological dysfunction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

ATP8A2 Gene-Disease associations (from GenCC):

cerebellar ataxia, intellectual disability, and dysequilibrium
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ATP8A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.092102915).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016529.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8A2	NM_016529.6	MANE Select	c.9C>A	p.Asn3Lys	missense	Exon 1 of 37	NP_057613.4
ATP8A2	NM_001411005.1		c.9C>A	p.Asn3Lys	missense	Exon 1 of 36	NP_001397934.1	A0A804HKW9
ATP8A2	NM_001411006.1		c.9C>A	p.Asn3Lys	missense	Exon 1 of 34	NP_001397935.1	A0A804HI09

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.9C>A	p.Asn3Lys	missense	Exon 1 of 37	ENSP00000371070.2	Q9NTI2-4
ATP8A2	ENST00000281620.11	TSL:1	n.9C>A		non_coding_transcript_exon	Exon 1 of 38	ENSP00000281620.7	F8W9B3
ATP8A2	ENST00000682472.1		c.9C>A	p.Asn3Lys	missense	Exon 1 of 36	ENSP00000508103.1	A0A804HKW9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1290654

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

635954

African (AFR)

AF:

0.00

AC:

AN:

26166

American (AMR)

AF:

0.00

AC:

AN:

24532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21960

East Asian (EAS)

AF:

0.00

AC:

AN:

26638

South Asian (SAS)

AF:

0.00

AC:

AN:

68266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5070

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1020392

Other (OTH)

AF:

0.00

AC:

AN:

51876

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.88

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.33

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.092

MetaSVM

Benign

-1.0

PhyloP100

1.3

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.050

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

0.93

Vest4

0.11

MutPred

0.20

Gain of MoRF binding (P = 0.0127)

MVP

0.42

MPC

0.62

ClinPred

0.059

GERP RS

1.6

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.056

gMVP

0.25

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over