chr13-25699294-G-A

Variant names:

• chr13-25699294-G-A
• rs202017613
• NM_016529.6:c.2333G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_016529.6(ATP8A2):​c.2333G>A​(p.Arg778Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,613,636 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R778W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: ATP8A2 NM_016529.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 10.0
• Publications: 9 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2591774).
• BP6: Variant 13-25699294-G-A is Benign according to our data. Variant chr13-25699294-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522654.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000401 (61/152220) while in subpopulation NFE AF = 0.000706 (48/68018). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.2333G>A	p.Arg778Gln	missense	Exon 25 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.2333G>A	p.Arg778Gln	missense	Exon 25 of 36	NP_001397934.1	A0A804HKW9
	ATP8A2	NM_001313741.1		c.2213G>A	p.Arg738Gln	missense	Exon 25 of 36	NP_001300670.1	Q9NTI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.2333G>A	p.Arg778Gln	missense	Exon 25 of 37	ENSP00000371070.2	Q9NTI2-4
	ATP8A2	ENST00000281620.11	TSL:1	n.*1960G>A		non_coding_transcript_exon	Exon 25 of 38	ENSP00000281620.7	F8W9B3
	ATP8A2	ENST00000491840.1	TSL:1	n.1204G>A		non_coding_transcript_exon	Exon 11 of 20

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000434 AC: 108 AN: 248764 AF XY: 0.000445

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000874

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000647

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000588 AC: 860 AN: 1461416 Hom.: 2 Cov.: 35 AF XY: 0.000605 AC XY: 440 AN XY: 726974

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.0000672 AC: 3 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.000682 AC: 758 AN: 1111762

Other (OTH) AF: 0.000431 AC: 26 AN: 60378

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74432

African (AFR) AF: 0.0000241 AC: 1 AN: 41526

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000684 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000254 AC: 1

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000314 AC: 38

EpiCase AF: 0.000764

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.066	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.12	D
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.015	D
Sift4G	Benign	0.063	T
Vest4		0.77
MVP		0.85
MPC		0.70
ClinPred		0.47	T
GERP RS		5.0
Varity_R		0.32
gMVP		0.76
Mutation Taster		=69/31	polymorphism

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: rs202017613; hg19: chr13-26273432;