13-25433839-G-A

Variant names:

• chr13-25433839-G-A
• rs7322916
• NM_016529.6:c.77-35138G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016529.6(ATP8A2):​c.77-35138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,030 control chromosomes in the GnomAD database, including 14,678 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14678 hom., cov: 32)
• Consequence: ATP8A2 NM_016529.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

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.77-35138G>A		intron	N/A	NP_057613.4
	ATP8A2	NM_001411005.1		c.77-35138G>A		intron	N/A	NP_001397934.1
	ATP8A2	NM_001411006.1		c.77-35138G>A		intron	N/A	NP_001397935.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.77-35138G>A		intron	N/A	ENSP00000371070.2
	ATP8A2	ENST00000281620.11	TSL:1	n.77-35138G>A		intron	N/A	ENSP00000281620.7
	ATP8A2	ENST00000682472.1		c.77-35138G>A		intron	N/A	ENSP00000508103.1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65082 AN: 151912 Hom.: 14675 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.429

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.428 AC: 65119 AN: 152030 Hom.: 14678 Cov.: 32 AF XY: 0.427 AC XY: 31729 AN XY: 74308

African (AFR) AF: 0.284 AC: 11759 AN: 41440

American (AMR) AF: 0.444 AC: 6773 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1475 AN: 3470

East Asian (EAS) AF: 0.588 AC: 3029 AN: 5148

South Asian (SAS) AF: 0.455 AC: 2199 AN: 4828

European-Finnish (FIN) AF: 0.448 AC: 4740 AN: 10580

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33726 AN: 67986

Other (OTH) AF: 0.429 AC: 904 AN: 2108

Alfa AF: 0.337 Hom.: 897

Bravo AF: 0.424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.9
DANN	Benign	0.65
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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: rs7322916; hg19: chr13-26007977;