chr13-25699239-G-A

Variant names:

• chr13-25699239-G-A
• rs35540339
• NM_016529.6:c.2278G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016529.6(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. 14/20 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 NM_016529.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.29
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	NM_016529.6	MANE Select	c.2278G>A	p.Val760Met	missense	Exon 25 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.2278G>A	p.Val760Met	missense	Exon 25 of 36	NP_001397934.1
	ATP8A2	NM_001313741.1		c.2158G>A	p.Val720Met	missense	Exon 25 of 36	NP_001300670.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.2278G>A	p.Val760Met	missense	Exon 25 of 37	ENSP00000371070.2
	ATP8A2	ENST00000281620.11	TSL:1	n.*1905G>A		non_coding_transcript_exon	Exon 25 of 38	ENSP00000281620.7
	ATP8A2	ENST00000491840.1	TSL:1	n.1149G>A		non_coding_transcript_exon	Exon 11 of 20

Frequencies

GnomAD3 genomes AF: 0.00856 AC: 1302 AN: 152152 Hom.: 19 Cov.: 32

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

GnomAD2 exomes AF: 0.00871 AC: 2167 AN: 248900 AF XY: 0.00867

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 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.: 30 AF XY: 0.0100 AC XY: 7287 AN XY: 726900

African (AFR) AF: 0.00105 AC: 35 AN: 33472

American (AMR) AF: 0.00307 AC: 137 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00350 AC: 301 AN: 86098

European-Finnish (FIN) AF: 0.0274 AC: 1461 AN: 53408

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.0112 AC: 12415 AN: 1111648

Other (OTH) AF: 0.00967 AC: 584 AN: 60384

GnomAD4 genome AF: 0.00854 AC: 1301 AN: 152270 Hom.: 19 Cov.: 32 AF XY: 0.00908 AC XY: 676 AN XY: 74462

African (AFR) AF: 0.00154 AC: 64 AN: 41564

American (AMR) AF: 0.00700 AC: 107 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4814

European-Finnish (FIN) AF: 0.0249 AC: 264 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 823 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00981 Hom.: 62

Bravo AF: 0.00634

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00202 AC: 8

ESP6500EA AF: 0.00974 AC: 81

ExAC AF: 0.00841 AC: 1017

Asia WGS AF: 0.000577 AC: 2 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

Submissions by phenotype

not provided Benign:4

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP8A2: BP4, BS1, BS2

Nov 16, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.076
Sift	Benign	0.070	T
Sift4G	Benign	0.14	T
Vest4		0.088
MVP		0.62
MPC		0.96
ClinPred		0.011	T
GERP RS		1.4
Varity_R		0.030
gMVP		0.38
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs35540339; hg19: chr13-26273377; COSMIC: COSV99029409;