rs12968116

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374385.1(ATP8B1):c.2855G>A(p.Arg952Gln) variant causes a missense change. The variant allele was found at a frequency of 0.105 in 1,613,884 control chromosomes in the GnomAD database, including 9,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.079 ( 644 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9194 hom. )

Consequence

ATP8B1
NM_001374385.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.05

Publications

53 publications found

Variant links:

Genes affected

ATP8B1 (HGNC:3706): (ATPase phospholipid transporting 8B1) This gene encodes a member of the P-type cation transport ATPase family, which belongs to the subfamily of aminophospholipid-transporting ATPases. The aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. Mutations in this gene may result in progressive familial intrahepatic cholestasis type 1 and in benign recurrent intrahepatic cholestasis. [provided by RefSeq, Jul 2008]

ATP8B1 links:

ATP8B1-AS1 (HGNC:56042): (ATP8B1 antisense RNA 1)

ATP8B1-AS1 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 (MetaRNN=0.0027029812).

BP6

Variant 18-57655270-C-T is Benign according to our data. Variant chr18-57655270-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8B1	NM_001374385.1 link	c.2855G>A	p.Arg952Gln	missense_variant	Exon 23 of 28	ENST00000648908.2	NP_001361314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908.2 link	c.2855G>A	p.Arg952Gln	missense_variant	Exon 23 of 28		NM_001374385.1	ENSP00000497896.1		O43520

Frequencies

GnomAD3 genomes

AF:

0.0794

AC:

12075

AN:

152112

Hom.:

643

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0278

Gnomad AMI

AF:

0.286

Gnomad AMR

AF:

0.0653

Gnomad ASJ

AF:

0.0857

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0536

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.0803

GnomAD2 exomes

AF:

0.0824

AC:

20731

AN:

251472

AF XY:

0.0839

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.0408

Gnomad ASJ exome

AF:

0.0821

Gnomad EAS exome

AF:

0.000489

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.0858

GnomAD4 exome

AF:

0.108

AC:

157146

AN:

1461654

Hom.:

9194

Cov.:

AF XY:

0.106

AC XY:

77069

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.0247

AC:

827

AN:

33480

American (AMR)

AF:

0.0435

AC:

1946

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0846

AC:

2212

AN:

26136

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.0501

AC:

4319

AN:

86256

European-Finnish (FIN)

AF:

0.113

AC:

6013

AN:

53414

Middle Eastern (MID)

AF:

0.0732

AC:

422

AN:

5768

European-Non Finnish (NFE)

AF:

0.122

AC:

135441

AN:

1111786

Other (OTH)

AF:

0.0985

AC:

5951

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

8245

16490

24736

32981

41226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4774

9548

14322

19096

23870

<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:

0.0793

AC:

12073

AN:

152230

Hom.:

644

Cov.:

AF XY:

0.0783

AC XY:

5827

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0278

AC:

1153

AN:

41532

American (AMR)

AF:

0.0652

AC:

997

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0857

AC:

297

AN:

3466

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0535

AC:

258

AN:

4824

European-Finnish (FIN)

AF:

0.107

AC:

1136

AN:

10594

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7782

AN:

68012

Other (OTH)

AF:

0.0795

AC:

168

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

568

1137

1705

2274

2842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.100

Hom.:

2878

Bravo

AF:

0.0748

TwinsUK

AF:

0.118

AC:

439

ALSPAC

AF:

0.122

AC:

472

ESP6500AA

AF:

0.0250

AC:

110

ESP6500EA

AF:

0.115

AC:

987

ExAC

AF:

0.0854

AC:

10375

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.109

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 23, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive familial intrahepatic cholestasis type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;D

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.12

N;N

PhyloP100

5.1

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.37

Sift

Benign

0.28

T;.

Sift4G

Benign

0.18

T;.

Polyphen

1.0

D;D

Vest4

0.17

ClinPred

0.011

GERP RS

5.9

Varity_R

0.37

gMVP

0.68

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over