NM_016529.6:c.1128C>G

Variant names:

• chr13-25553863-C-G
• rs546968533
• NM_016529.6:c.1128C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_016529.6(ATP8A2):​c.1128C>G​(p.Ile376Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. I376I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP8A2 NM_016529.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.57
• Publications: 14 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a site Involved in the release of the transported lipid into the cytosolic leaflet (size 0) in uniprot entity AT8A2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 13-25553863-C-G is Pathogenic according to our data. Variant chr13-25553863-C-G is described in CliVar as Pathogenic. Clinvar id is 50946.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-25553863-C-G is described in CliVar as Pathogenic. Clinvar id is 50946.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-25553863-C-G is described in CliVar as Pathogenic. Clinvar id is 50946.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-25553863-C-G is described in CliVar as Pathogenic. Clinvar id is 50946.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-25553863-C-G is described in CliVar as Pathogenic. Clinvar id is 50946.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-25553863-C-G is described in CliVar as Pathogenic. Clinvar id is 50946.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-25553863-C-G is described in CliVar as Pathogenic. Clinvar id is 50946.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8A2	NM_016529.6	c.1128C>G	p.Ile376Met	missense_variant	Exon 12 of 37	ENST00000381655.7	NP_057613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8A2	ENST00000381655.7	c.1128C>G	p.Ile376Met	missense_variant	Exon 12 of 37	1	NM_016529.6	ENSP00000371070.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 Pathogenic:1

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.72	D
PhyloP100		1.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.017	D;D
Vest4		0.83
MutPred		0.66		.;Loss of helix (P = 0.1299);
MVP		0.88
MPC		1.5
ClinPred		0.99	D
GERP RS		2.2
Varity_R		0.53
gMVP		0.94
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs546968533; hg19: chr13-26128001;