Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016529.6(ATP8A2):c.3075A>G(p.Lys1025Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00393 in 1,584,032 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 21 hom. )

Consequence

ATP8A2
NM_016529.6 splice_region, synonymous

Scores

Splicing: ADA: 0.00009621

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.89

Publications

5 publications found

Variant links:

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

ATP8A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 13-25860860-A-G is Benign according to our data. Variant chr13-25860860-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 218739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00318 (484/152318) while in subpopulation NFE AF = 0.00544 (370/68034). AF 95% confidence interval is 0.00498. There are 0 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP8A2	NM_016529.6	MANE Select	c.3075A>G	p.Lys1025Lys	splice_region synonymous	Exon 32 of 37	NP_057613.4
ATP8A2	NM_001411005.1		c.3000A>G	p.Lys1000Lys	splice_region synonymous	Exon 31 of 36	NP_001397934.1
ATP8A2	NM_001313741.1		c.2880A>G	p.Lys960Lys	splice_region synonymous	Exon 31 of 36	NP_001300670.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.3075A>G	p.Lys1025Lys	splice_region synonymous	Exon 32 of 37	ENSP00000371070.2
ATP8A2	ENST00000281620.11	TSL:1	n.*2893A>G		splice_region non_coding_transcript_exon	Exon 33 of 38	ENSP00000281620.7
ATP8A2	ENST00000491840.1	TSL:1	n.1946A>G		splice_region non_coding_transcript_exon	Exon 18 of 20

Frequencies

GnomAD3 genomes

AF:

0.00318

AC:

484

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00545

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00304

AC:

660

AN:

216988

AF XY:

0.00312

show subpopulations

Gnomad AFR exome

AF:

0.00109

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00373

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.00509

GnomAD4 exome

AF:

0.00401

AC:

5745

AN:

1431714

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

2858

AN XY:

710880

show subpopulations

African (AFR)

AF:

0.000876

AC:

AN:

33120

American (AMR)

AF:

0.00264

AC:

112

AN:

42364

Ashkenazi Jewish (ASJ)

AF:

0.00445

AC:

114

AN:

25630

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39352

South Asian (SAS)

AF:

0.000625

AC:

AN:

83216

European-Finnish (FIN)

AF:

0.00262

AC:

137

AN:

52212

Middle Eastern (MID)

AF:

0.00306

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.00458

AC:

4996

AN:

1091066

Other (OTH)

AF:

0.00485

AC:

287

AN:

59200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

239

478

716

955

1194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00318

AC:

484

AN:

152318

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41570

American (AMR)

AF:

0.00262

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00544

AC:

370

AN:

68034

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00449

Hom.:

Bravo

AF:

0.00322

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

3.9

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000096

dbscSNV1_RF

Benign

0.028

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs62636611

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over