rs975508

Variant names:

• chr13-25991448-A-G
• rs975508
• NM_016529.6:c.3378-21083A>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.3378-21083A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,940 control chromosomes in the GnomAD database, including 13,004 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 0.41 (13004 hom., cov: 32)
• Consequence: ATP8A2 NM_016529.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.516
• Publications: 9 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 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.3378-21083A>G		intron	N/A	NP_057613.4
	ATP8A2	NM_001411005.1		c.3303-21083A>G		intron	N/A	NP_001397934.1
	ATP8A2	NM_001313741.1		c.3183-21083A>G		intron	N/A	NP_001300670.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.3378-21083A>G		intron	N/A	ENSP00000371070.2
	ATP8A2	ENST00000281620.11	TSL:1	n.*3196-21083A>G		intron	N/A	ENSP00000281620.7
	ATP8A2	ENST00000682472.1		c.3303-21083A>G		intron	N/A	ENSP00000508103.1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62025 AN: 151822 Hom.: 12986 Cov.: 32

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.416

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

GnomAD4 genome AF: 0.409 AC: 62085 AN: 151940 Hom.: 13004 Cov.: 32 AF XY: 0.403 AC XY: 29949 AN XY: 74260

African (AFR) AF: 0.405 AC: 16759 AN: 41416

American (AMR) AF: 0.361 AC: 5506 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1795 AN: 3466

East Asian (EAS) AF: 0.175 AC: 904 AN: 5158

South Asian (SAS) AF: 0.405 AC: 1948 AN: 4804

European-Finnish (FIN) AF: 0.391 AC: 4130 AN: 10574

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29531 AN: 67940

Other (OTH) AF: 0.420 AC: 887 AN: 2114

Alfa AF: 0.427 Hom.: 59466

Bravo AF: 0.402

Asia WGS AF: 0.313 AC: 1093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.29
PhyloP100		-0.52
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: rs975508; hg19: chr13-26565586;