13-25372284-C-G

Variant names:

• chr13-25372284-C-G
• rs1056041432
• NM_016529.6:c.72C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016529.6(ATP8A2):​c.72C>G​(p.Ser24Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000505 in 1,189,038 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. S24S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: ATP8A2 NM_016529.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.112
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.72C>G	p.Ser24Ser	synonymous	Exon 1 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.72C>G	p.Ser24Ser	synonymous	Exon 1 of 36	NP_001397934.1	A0A804HKW9
	ATP8A2	NM_001411006.1		c.72C>G	p.Ser24Ser	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.72C>G	p.Ser24Ser	synonymous	Exon 1 of 37	ENSP00000371070.2	Q9NTI2-4
	ATP8A2	ENST00000281620.11	TSL:1	n.72C>G		non_coding_transcript_exon	Exon 1 of 38	ENSP00000281620.7	F8W9B3
	ATP8A2	ENST00000682472.1		c.72C>G	p.Ser24Ser	synonymous	Exon 1 of 36	ENSP00000508103.1	A0A804HKW9

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 4 AN: 149680 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000192 AC: 2 AN: 1039358 Hom.: 0 Cov.: 31 AF XY: 0.00000193 AC XY: 1 AN XY: 517120

African (AFR) AF: 0.00 AC: 0 AN: 19976

American (AMR) AF: 0.00 AC: 0 AN: 22250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17286

East Asian (EAS) AF: 0.00 AC: 0 AN: 14886

South Asian (SAS) AF: 0.00 AC: 0 AN: 67660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3942

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818928

Other (OTH) AF: 0.0000247 AC: 1 AN: 40484

GnomAD4 genome AF: 0.0000267 AC: 4 AN: 149680 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73126

African (AFR) AF: 0.0000971 AC: 4 AN: 41192

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5014

South Asian (SAS) AF: 0.00 AC: 0 AN: 4662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67164

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000304 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.81
PhyloP100		-0.11
PromoterAI		-0.0012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.81		Position offset: 0

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

Other links and lift over

dbSNP: rs1056041432; hg19: chr13-25946422;