13-25692740-C-T

Variant names:

• chr13-25692740-C-T
• rs7989017
• NM_016529.6:c.2212-6433C>T

Variant summary

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

The NM_016529.6(ATP8A2):​c.2212-6433C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 151,946 control chromosomes in the GnomAD database, including 6,067 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 0.28 (6067 hom., cov: 32)
• Consequence: ATP8A2 NM_016529.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.929
• Publications: 1 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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.447 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	NM_016529.6	MANE Select	c.2212-6433C>T		intron	N/A	NP_057613.4
	ATP8A2	NM_001411005.1		c.2212-6433C>T		intron	N/A	NP_001397934.1	A0A804HKW9
	ATP8A2	NM_001313741.1		c.2092-6433C>T		intron	N/A	NP_001300670.1	Q9NTI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.2212-6433C>T		intron	N/A	ENSP00000371070.2	Q9NTI2-4
	ATP8A2	ENST00000281620.11	TSL:1	n.*1839-6433C>T		intron	N/A	ENSP00000281620.7	F8W9B3
	ATP8A2	ENST00000491840.1	TSL:1	n.1083-6433C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42019 AN: 151826 Hom.: 6063 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.277 AC: 42056 AN: 151946 Hom.: 6067 Cov.: 32 AF XY: 0.282 AC XY: 20967 AN XY: 74276

African (AFR) AF: 0.268 AC: 11118 AN: 41420

American (AMR) AF: 0.274 AC: 4182 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 876 AN: 3464

East Asian (EAS) AF: 0.439 AC: 2265 AN: 5154

South Asian (SAS) AF: 0.463 AC: 2228 AN: 4814

European-Finnish (FIN) AF: 0.306 AC: 3228 AN: 10562

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17436 AN: 67950

Other (OTH) AF: 0.264 AC: 556 AN: 2110

Alfa AF: 0.272 Hom.: 3037

Bravo AF: 0.272

Asia WGS AF: 0.407 AC: 1417 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.056
DANN	Benign	0.83
PhyloP100		-0.93
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: rs7989017; hg19: chr13-26266878;