chr13-25469058-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 547903.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8A2	NM_016529.6 link	c.158C>T	p.Ala53Val	missense_variant	Exon 2 of 37	ENST00000381655.7	NP_057613.4	Q9NTI2-4Q6ZU25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7 link	c.158C>T	p.Ala53Val	missense_variant	Exon 2 of 37	1	NM_016529.6	ENSP00000371070.2		Q9NTI2-4

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

GnomAD3 exomes

AF:

0.00107

AC:

267

AN:

249280

Hom.:

AF XY:

0.00109

AC XY:

147

AN XY:

135352

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00930

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000631

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152240

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000985

Gnomad4 OTH

AF:

0.00

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP8A2: BP4, BS2 -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

Uncertain:1

Jan 12, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATP8A2-related disorder

Benign:1

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0057

.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.021

Sift

Benign

0.34

T;T

Sift4G

Benign

0.29

T;T

Vest4

0.15

MVP

0.46

MPC

0.54

ClinPred

0.022

GERP RS

1.5

Varity_R

0.073

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over