rs41291650

Positions:

• chr13-25860879-T-C

Variant summary

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

The NM_016529.6(ATP8A2):​c.3075+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,537,948 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (69 hom.)
• Consequence: ATP8A2 NM_016529.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.339

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=-0.79).
• BP6: Variant 13-25860879-T-C is Benign according to our data. Variant chr13-25860879-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 446078.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 = 0.0056 (854/152372) while in subpopulation NFE AF= 0.00969 (659/68042). AF 95% confidence interval is 0.00907. There are 11 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8A2	NM_016529.6	c.3075+19T>C		intron_variant		ENST00000381655.7	NP_057613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7	c.3075+19T>C		intron_variant		1	NM_016529.6	ENSP00000371070

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 854 AN: 152254 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00968

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00516 AC: 1014 AN: 196622 Hom.: 6 AF XY: 0.00554 AC XY: 582 AN XY: 105048

Gnomad AFR exome AF: 0.000860

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00610

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00480

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00886

Gnomad OTH exome AF: 0.00660

GnomAD4 exome AF: 0.00831 AC: 11512 AN: 1385576 Hom.: 69 Cov.: 24 AF XY: 0.00821 AC XY: 5656 AN XY: 689082

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00189

Gnomad4 ASJ exome AF: 0.00652

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00465

Gnomad4 FIN exome AF: 0.00173

Gnomad4 NFE exome AF: 0.00982

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00560 AC: 854 AN: 152372 Hom.: 11 Cov.: 33 AF XY: 0.00507 AC XY: 378 AN XY: 74514

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00969

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00674 Hom.: 1

Bravo AF: 0.00578

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 11, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.4
DANN	Benign	0.79

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: rs41291650; hg19: chr13-26435017;