rs62636611

Positions:

• chr13-25860860-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000381655.7(ATP8A2):​c.3075A>G​(p.Lys1025=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00393 in 1,584,032 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (21 hom.)
• Consequence: ATP8A2 ENST00000381655.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.00009621
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.89

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 13-25860860-A-G is Benign according to our data. Variant chr13-25860860-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 218739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00318 (484/152318) while in subpopulation NFE AF= 0.00544 (370/68034). AF 95% confidence interval is 0.00498. There are 0 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8A2	NM_016529.6	c.3075A>G	p.Lys1025=	splice_region_variant, synonymous_variant	32/37	ENST00000381655.7	NP_057613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7	c.3075A>G	p.Lys1025=	splice_region_variant, synonymous_variant	32/37	1	NM_016529.6	ENSP00000371070

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 484 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00304 AC: 660 AN: 216988 Hom.: 3 AF XY: 0.00312 AC XY: 364 AN XY: 116742

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00373

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000737

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00509

GnomAD4 exome AF: 0.00401 AC: 5745 AN: 1431714 Hom.: 21 Cov.: 27 AF XY: 0.00402 AC XY: 2858 AN XY: 710880

Gnomad4 AFR exome AF: 0.000876

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00445

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000625

Gnomad4 FIN exome AF: 0.00262

Gnomad4 NFE exome AF: 0.00458

Gnomad4 OTH exome AF: 0.00485

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74478

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00544

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00488 Hom.: 1

Bravo AF: 0.00322

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ATP8A2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 17, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.028
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: rs62636611; hg19: chr13-26434998;