rs371560228

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_016529.6(ATP8A2):c.3439C>T(p.Arg1147Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,515,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

ATP8A2
NM_016529.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.13

Publications

3 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41186732).

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.3439C>T	p.Arg1147Trp	missense	Exon 36 of 37	NP_057613.4
ATP8A2	NM_001411005.1		c.3364C>T	p.Arg1122Trp	missense	Exon 35 of 36	NP_001397934.1	A0A804HKW9
ATP8A2	NM_001313741.1		c.3244C>T	p.Arg1082Trp	missense	Exon 35 of 36	NP_001300670.1	Q9NTI2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.3439C>T	p.Arg1147Trp	missense	Exon 36 of 37	ENSP00000371070.2	Q9NTI2-4
ATP8A2	ENST00000281620.11	TSL:1	n.*3257C>T		non_coding_transcript_exon	Exon 37 of 38	ENSP00000281620.7	F8W9B3
ATP8A2	ENST00000281620.11	TSL:1	n.*3257C>T		3_prime_UTR	Exon 37 of 38	ENSP00000281620.7	F8W9B3

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000822

AC:

AN:

121692

AF XY:

0.0000761

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1363828

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

671342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28998

American (AMR)

AF:

0.0000344

AC:

AN:

29034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24022

East Asian (EAS)

AF:

0.00

AC:

AN:

32808

South Asian (SAS)

AF:

0.00

AC:

AN:

73836

European-Finnish (FIN)

AF:

0.0000411

AC:

AN:

48676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.0000742

AC:

AN:

1064386

Other (OTH)

AF:

0.0000177

AC:

AN:

56498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151852

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41334

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000128

AC:

ExAC

AF:

0.0000326

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.057

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.070

MetaRNN

Benign

0.41

MetaSVM

Uncertain

-0.26

PhyloP100

5.1

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.38

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Vest4

0.46

MVP

0.82

MPC

2.1

ClinPred

0.85

GERP RS

5.8

Varity_R

0.14

gMVP

0.57

Mutation Taster

=25/75

disease causing

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over