rs201822155

Variant names:

• chr13-25579812-G-A
• rs201822155
• NM_016529.6:c.1872G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-25579812-G-A
• chr13-25579812-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016529.6(ATP8A2):​c.1872G>A​(p.Leu624Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ATP8A2 NM_016529.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 0 publications found

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]

ATP8A2 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016529.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	NM_016529.6	MANE Select	c.1872G>A	p.Leu624Leu	synonymous	Exon 22 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.1872G>A	p.Leu624Leu	synonymous	Exon 22 of 36	NP_001397934.1
	ATP8A2	NM_001313741.1		c.1752G>A	p.Leu584Leu	synonymous	Exon 22 of 36	NP_001300670.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.1872G>A	p.Leu624Leu	synonymous	Exon 22 of 37	ENSP00000371070.2
	ATP8A2	ENST00000281620.11	TSL:1	n.*1499G>A		non_coding_transcript_exon	Exon 22 of 38	ENSP00000281620.7
	ATP8A2	ENST00000491840.1	TSL:1	n.623G>A		non_coding_transcript_exon	Exon 7 of 20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31854

American (AMR) AF: 0.00 AC: 0 AN: 36206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23570

East Asian (EAS) AF: 0.00 AC: 0 AN: 36530

South Asian (SAS) AF: 0.00 AC: 0 AN: 75852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42170

Middle Eastern (MID) AF: 0.000224 AC: 1 AN: 4456

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085864

Other (OTH) AF: 0.00 AC: 0 AN: 58278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.0
DANN	Benign	0.75
PhyloP100		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201822155; hg19: chr13-26153950;