chr13-25469044-A-C

Position:

• chr13-25469044-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016529.6(ATP8A2):​c.144A>C​(p.Gly48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,613,836 control chromosomes in the GnomAD database, including 37,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4203 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33361 hom.)
• Consequence: ATP8A2 NM_016529.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.18

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 13-25469044-A-C is Benign according to our data. Variant chr13-25469044-A-C is described in ClinVar as [Benign]. Clinvar id is 128488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8A2	NM_016529.6	c.144A>C	p.Gly48=	synonymous_variant	2/37	ENST00000381655.7	NP_057613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7	c.144A>C	p.Gly48=	synonymous_variant	2/37	1	NM_016529.6	ENSP00000371070

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34414 AN: 152058 Hom.: 4188 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.186 AC: 46331 AN: 249296 Hom.: 4749 AF XY: 0.185 AC XY: 25075 AN XY: 135330

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.0907

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.210 AC: 307205 AN: 1461662 Hom.: 33361 Cov.: 34 AF XY: 0.208 AC XY: 151457 AN XY: 727140

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.227 AC: 34473 AN: 152174 Hom.: 4203 Cov.: 33 AF XY: 0.221 AC XY: 16463 AN XY: 74394

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.188

Alfa AF: 0.214 Hom.: 5679

Bravo AF: 0.224

Asia WGS AF: 0.151 AC: 524 AN: 3478

EpiCase AF: 0.205

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.78

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: rs7317185; hg19: chr13-26043182; COSMIC: COSV54943308;