Genetic Variant ATP8A2:p.Ala53Val (chr13-25469058-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016529.6(ATP8A2):c.158C>T(p.Ala53Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,613,980 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 4 hom. )

Consequence

ATP8A2
NM_016529.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.84

Publications

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

ATP8A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004190415).

BP6

Variant 13-25469058-C-T is Benign according to our data. Variant chr13-25469058-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547903.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000716 (109/152240) while in subpopulation NFE AF = 0.000985 (67/68034). AF 95% confidence interval is 0.000795. There are 2 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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
ATP8A2	NM_016529.6	MANE Select	c.158C>T	p.Ala53Val	missense	Exon 2 of 37	NP_057613.4
ATP8A2	NM_001411005.1		c.158C>T	p.Ala53Val	missense	Exon 2 of 36	NP_001397934.1
ATP8A2	NM_001313741.1		c.38C>T	p.Ala13Val	missense	Exon 2 of 36	NP_001300670.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.158C>T	p.Ala53Val	missense	Exon 2 of 37	ENSP00000371070.2
ATP8A2	ENST00000281620.11	TSL:1	n.158C>T		non_coding_transcript_exon	Exon 2 of 38	ENSP00000281620.7
ATP8A2	ENST00000682472.1		c.158C>T	p.Ala53Val	missense	Exon 2 of 36	ENSP00000508103.1

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00107

AC:

267

AN:

249280

AF XY:

0.00109

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000690

AC:

1009

AN:

1461740

Hom.:

Cov.:

AF XY:

0.000723

AC XY:

526

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00930

AC:

243

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000631

AC:

702

AN:

1111894

Other (OTH)

AF:

0.000778

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

120

181

241

301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000716

AC:

109

AN:

152240

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41472

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00157

Hom.:

Bravo

AF:

0.000691

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000835

AC:

ExAC

AF:

0.000951

AC:

115

EpiCase

AF:

0.00120

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

ATP8A2-related disorder (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0057

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.69

M_CAP

Benign

0.070

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.94

PhyloP100

2.8

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.50

REVEL

Benign

0.021

Sift

Benign

0.34

Sift4G

Benign

0.29

Vest4

0.15

MVP

0.46

MPC

0.54

ClinPred

0.022

GERP RS

1.5

PromoterAI

-0.077

Neutral

(source)

Varity_R

0.073

gMVP

0.44

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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