rs369291641

Positions:

• chr13-25372298-G-A
• chr13-25372298-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_016529.6(ATP8A2):​c.76+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,464,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: ATP8A2 NM_016529.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.269

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 13-25372298-G-A is Benign according to our data. Variant chr13-25372298-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446062.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr13-25372298-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8A2	NM_016529.6	c.76+10G>A		intron_variant		ENST00000381655.7	NP_057613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7	c.76+10G>A		intron_variant		1	NM_016529.6	ENSP00000371070

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 151778 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00117 AC: 105 AN: 89790 Hom.: 0 AF XY: 0.00117 AC XY: 59 AN XY: 50576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000749

Gnomad ASJ exome AF: 0.00769

Gnomad EAS exome AF: 0.000370

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00127 AC: 1671 AN: 1313054 Hom.: 0 Cov.: 31 AF XY: 0.00131 AC XY: 848 AN XY: 647602

Gnomad4 AFR exome AF: 0.000615

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00810

Gnomad4 EAS exome AF: 0.0000370

Gnomad4 SAS exome AF: 0.0000138

Gnomad4 FIN exome AF: 0.0000432

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00101 AC: 154 AN: 151778 Hom.: 0 Cov.: 32 AF XY: 0.000971 AC XY: 72 AN XY: 74146

Gnomad4 AFR AF: 0.000652

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.000960

Bravo AF: 0.00102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 26, 2017	- -

ATP8A2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs369291641; hg19: chr13-25946436;