13-25468959-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_016529.6(ATP8A2):c.77-18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,054 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: ATP8A2 NM_016529.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.891

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 13-25468959-T-G is Benign according to our data. Variant chr13-25468959-T-G is described in ClinVar as [Benign]. Clinvar id is 1599231.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00293 (4286/1460758) while in subpopulation NFE AF= 0.00349 (3875/1111276). AF 95% confidence interval is 0.00339. There are 9 homozygotes in gnomad4_exome. There are 2032 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8A2	NM_016529.6	c.77-18T>G		intron_variant		ENST00000381655.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8A2	ENST00000381655.7	c.77-18T>G		intron_variant		1	NM_016529.6

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00189 AC: 469 AN: 248168 Hom.: 1 AF XY: 0.00206 AC XY: 278 AN XY: 134762

Gnomad AFR exome AF: 0.000907

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00515

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00293 AC: 4286 AN: 1460758 Hom.: 9 Cov.: 31 AF XY: 0.00280 AC XY: 2032 AN XY: 726640

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00543

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00163 AC: 249 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74468

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000863 Hom.: 0

Bravo AF: 0.00132

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.4
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199807614; hg19: chr13-26043097;