chr13-25699239-G-A

Position:

chr13-25699239-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000381655.7(ATP8A2):c.2278G>A(p.Val760Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,540 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 19 hom., cov: 32)

Exomes 𝑓: 0.010 ( 113 hom. )

Consequence

ATP8A2
ENST00000381655.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.29

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048558116).

BP6

Variant 13-25699239-G-A is Benign according to our data. Variant chr13-25699239-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 376887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00854 (1301/152270) while in subpopulation NFE AF= 0.0121 (823/68024). AF 95% confidence interval is 0.0114. There are 19 homozygotes in gnomad4. There are 676 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8A2	NM_016529.6 linkuse as main transcript	c.2278G>A	p.Val760Met	missense_variant	25/37	ENST00000381655.7	NP_057613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7 linkuse as main transcript	c.2278G>A	p.Val760Met	missense_variant	25/37	1	NM_016529.6	ENSP00000371070		Q9NTI2-4

Frequencies

GnomAD3 genomes

AF:

0.00856

AC:

1302

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00701

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.0249

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00871

AC:

2167

AN:

248900

Hom.:

AF XY:

0.00867

AC XY:

1170

AN XY:

135018

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00297

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00344

Gnomad FIN exome

AF:

0.0257

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.0102

AC:

14947

AN:

1461270

Hom.:

113

Cov.:

AF XY:

0.0100

AC XY:

7287

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00307

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00350

Gnomad4 FIN exome

AF:

0.0274

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00967

GnomAD4 genome

AF:

0.00854

AC:

1301

AN:

152270

Hom.:

Cov.:

AF XY:

0.00908

AC XY:

676

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00700

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.0249

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00634

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00202

AC:

ESP6500EA

AF:

0.00974

AC:

ExAC

AF:

0.00841

AC:

1017

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.00820

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ATP8A2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 16, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.010

.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.59

D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.97

N;.

REVEL

Benign

0.076

Sift

Benign

0.070

T;.

Sift4G

Benign

0.14

T;T

Vest4

0.088

MVP

0.62

MPC

0.96

ClinPred

0.011

GERP RS

1.4

Varity_R

0.030

gMVP

0.38

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

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