NM_016529.6:c.69G>A

Variant names:

• chr13-25372281-G-A
• rs937608699
• NM_016529.6:c.69G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_016529.6(ATP8A2):​c.69G>A​(p.Ser23Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,322,612 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. Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ATP8A2 NM_016529.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.177
• 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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP7: Synonymous conserved (PhyloP=0.177 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	NM_016529.6	MANE Select	c.69G>A	p.Ser23Ser	synonymous	Exon 1 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.69G>A	p.Ser23Ser	synonymous	Exon 1 of 36	NP_001397934.1	A0A804HKW9
	ATP8A2	NM_001411006.1		c.69G>A	p.Ser23Ser	synonymous	Exon 1 of 34	NP_001397935.1	A0A804HI09

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.69G>A	p.Ser23Ser	synonymous	Exon 1 of 37	ENSP00000371070.2	Q9NTI2-4
	ATP8A2	ENST00000281620.11	TSL:1	n.69G>A		non_coding_transcript_exon	Exon 1 of 38	ENSP00000281620.7	F8W9B3
	ATP8A2	ENST00000682472.1		c.69G>A	p.Ser23Ser	synonymous	Exon 1 of 36	ENSP00000508103.1	A0A804HKW9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1322612 Hom.: 0 Cov.: 32 AF XY: 0.00000153 AC XY: 1 AN XY: 651960

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 26272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22742

East Asian (EAS) AF: 0.0000368 AC: 1 AN: 27168

South Asian (SAS) AF: 0.00 AC: 0 AN: 72888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4886

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041596

Other (OTH) AF: 0.0000186 AC: 1 AN: 53870

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	16
DANN	Uncertain	0.98
PhyloP100		0.18
PromoterAI		0.0024	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs937608699; hg19: chr13-25946419;