13-25372280-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_016529.6(ATP8A2):c.68C>G(p.Ser23Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,431,836 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 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

ATP8A2
NM_016529.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.736

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000264 (40/151446) while in subpopulation NFE AF= 0.000531 (36/67752). AF 95% confidence interval is 0.000394. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8A2	NM_016529.6 link	c.68C>G	p.Ser23Trp	missense_variant	Exon 1 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.68C>G	p.Ser23Trp	missense_variant	Exon 1 of 37	1	NM_016529.6	ENSP00000371070.2		Q9NTI2-4

Frequencies

GnomAD3 genomes

AF:

0.000264

AC:

AN:

151340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000971

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000531

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000212

AC:

AN:

94198

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

52630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000440

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000503

AC:

644

AN:

1280390

Hom.:

Cov.:

AF XY:

0.000508

AC XY:

321

AN XY:

631776

show subpopulations

Gnomad4 AFR exome

AF:

0.0000795

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000375

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000617

Gnomad4 OTH exome

AF:

0.000156

GnomAD4 genome

AF:

0.000264

AC:

AN:

151446

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

AN XY:

74054

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000971

Gnomad4 NFE

AF:

0.000531

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.0000694

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.000122

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 23 of the ATP8A2 protein (p.Ser23Trp). This variant is present in population databases (rs200068509, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ATP8A2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.68C>G (p.S23W) alteration is located in exon 1 (coding exon 1) of the ATP8A2 gene. This alteration results from a C to G substitution at nucleotide position 68, causing the serine (S) at amino acid position 23 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.45

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.87

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.70

REVEL

Benign

0.055

Sift

Benign

0.087

Sift4G

Uncertain

0.020

Vest4

0.29

MVP

0.59

MPC

1.2

ClinPred

0.26

GERP RS

2.5

Varity_R

0.079

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 0

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