rs200068509

Variant names:

• chr13-25372280-C-G
• rs200068509
• NM_016529.6:c.68C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-25372280-C-G
• chr13-25372280-C-A
• chr13-25372280-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_016529.6(ATP8A2):​c.68C>G​(p.Ser23Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,431,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: ATP8A2 NM_016529.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.736
• Publications: 1 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.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000264 (40/151446) while in subpopulation NFE AF = 0.000531 (36/67752). AF 95% confidence interval is 0.000394. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.68C>G	p.Ser23Trp	missense	Exon 1 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.68C>G	p.Ser23Trp	missense	Exon 1 of 36	NP_001397934.1	A0A804HKW9
	ATP8A2	NM_001411006.1		c.68C>G	p.Ser23Trp	missense	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.68C>G	p.Ser23Trp	missense	Exon 1 of 37	ENSP00000371070.2	Q9NTI2-4
	ATP8A2	ENST00000281620.11	TSL:1	n.68C>G		non_coding_transcript_exon	Exon 1 of 38	ENSP00000281620.7	F8W9B3
	ATP8A2	ENST00000682472.1		c.68C>G	p.Ser23Trp	missense	Exon 1 of 36	ENSP00000508103.1	A0A804HKW9

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151340 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000971

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000531

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000212 AC: 20 AN: 94198 AF XY: 0.000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000440

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000512

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000503 AC: 644 AN: 1280390 Hom.: 0 Cov.: 31 AF XY: 0.000508 AC XY: 321 AN XY: 631776

African (AFR) AF: 0.0000795 AC: 2 AN: 25166

American (AMR) AF: 0.00 AC: 0 AN: 25266

Ashkenazi Jewish (ASJ) AF: 0.000375 AC: 8 AN: 21358

East Asian (EAS) AF: 0.00 AC: 0 AN: 24206

South Asian (SAS) AF: 0.00 AC: 0 AN: 72122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44120

Middle Eastern (MID) AF: 0.000426 AC: 2 AN: 4692

European-Non Finnish (NFE) AF: 0.000617 AC: 624 AN: 1012094

Other (OTH) AF: 0.000156 AC: 8 AN: 51366

GnomAD4 genome AF: 0.000264 AC: 40 AN: 151446 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 74054

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.0000971 AC: 1 AN: 10294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000531 AC: 36 AN: 67752

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.0000694 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.000122 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.74
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.055
Sift	Benign	0.087	T
Sift4G	Uncertain	0.020	D
Vest4		0.29
MVP		0.59
MPC		1.2
ClinPred		0.26	T
GERP RS		2.5
PromoterAI		-0.086	Neutral
Varity_R		0.079
gMVP		0.33
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 0

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

Other links and lift over

dbSNP: rs200068509; hg19: chr13-25946418;