13-25876426-A-G

Variant names:

• chr13-25876426-A-G
• rs306395
• NM_016529.6:c.3183+14018A>G

Variant summary

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

The NM_016529.6(ATP8A2):​c.3183+14018A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 152,060 control chromosomes in the GnomAD database, including 19,962 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 0.50 (19962 hom., cov: 32)
• Consequence: ATP8A2 NM_016529.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.949
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8A2	NM_016529.6	c.3183+14018A>G		intron_variant	Intron 33 of 36	ENST00000381655.7	NP_057613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7	c.3183+14018A>G		intron_variant	Intron 33 of 36	1	NM_016529.6	ENSP00000371070.2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76234 AN: 151942 Hom.: 19902 Cov.: 32

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.489

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

GnomAD4 genome AF: 0.502 AC: 76359 AN: 152060 Hom.: 19962 Cov.: 32 AF XY: 0.499 AC XY: 37068 AN XY: 74318

African (AFR) AF: 0.639 AC: 26484 AN: 41452

American (AMR) AF: 0.561 AC: 8572 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1458 AN: 3468

East Asian (EAS) AF: 0.452 AC: 2336 AN: 5172

South Asian (SAS) AF: 0.423 AC: 2038 AN: 4816

European-Finnish (FIN) AF: 0.383 AC: 4044 AN: 10568

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29858 AN: 67980

Other (OTH) AF: 0.492 AC: 1041 AN: 2114

Alfa AF: 0.474 Hom.: 14705

Bravo AF: 0.522

Asia WGS AF: 0.549 AC: 1910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.4
DANN	Benign	0.33
PhyloP100		0.95
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: rs306395; hg19: chr13-26450564; COSMIC: COSV54974002;