2-168973818-A-G

Variant names:

Variant summary

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

The NM_003742.4(ABCB11):c.1331T>C(p.Val444Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,610,750 control chromosomes in the GnomAD database, including 282,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25038 hom., cov: 30)

Exomes 𝑓: 0.59 ( 257725 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.39

Publications

164 publications found

Variant links:

Genes affected

ABCB11 (HGNC:42): (ATP binding cassette subfamily B member 11) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is the major canalicular bile salt export pump in man. Mutations in this gene cause a form of progressive familial intrahepatic cholestases which are a group of inherited disorders with severe cholestatic liver disease from early infancy. [provided by RefSeq, Jul 2008]

ABCB11 Gene-Disease associations (from GenCC):

progressive familial intrahepatic cholestasis type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
benign recurrent intrahepatic cholestasis type 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ABCB11 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=2.0099598E-5).

BP6

Variant 2-168973818-A-G is Benign according to our data. Variant chr2-168973818-A-G is described in ClinVar as Benign. ClinVar VariationId is 194214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.1331T>C	p.Val444Ala	missense_variant	Exon 13 of 28	ENST00000650372.1	NP_003733.2	O95342

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1 link	c.1331T>C	p.Val444Ala	missense_variant	Exon 13 of 28		NM_003742.4	ENSP00000497931.1		O95342

Frequencies

GnomAD3 genomes

AF:

0.572

AC:

86689

AN:

151500

Hom.:

25023

Cov.:

show subpopulations

Gnomad AFR

AF:

0.567

Gnomad AMI

AF:

0.660

Gnomad AMR

AF:

0.463

Gnomad ASJ

AF:

0.575

Gnomad EAS

AF:

0.717

Gnomad SAS

AF:

0.567

Gnomad FIN

AF:

0.511

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.597

Gnomad OTH

AF:

0.580

GnomAD2 exomes

AF:

0.569

AC:

141494

AN:

248542

AF XY:

0.574

show subpopulations

Gnomad AFR exome

AF:

0.571

Gnomad AMR exome

AF:

0.423

Gnomad ASJ exome

AF:

0.558

Gnomad EAS exome

AF:

0.728

Gnomad FIN exome

AF:

0.515

Gnomad NFE exome

AF:

0.599

Gnomad OTH exome

AF:

0.564

GnomAD4 exome

AF:

0.593

AC:

864780

AN:

1459132

Hom.:

257725

Cov.:

AF XY:

0.592

AC XY:

429695

AN XY:

725906

show subpopulations

African (AFR)

AF:

0.578

AC:

19267

AN:

33362

American (AMR)

AF:

0.424

AC:

18935

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.563

AC:

14663

AN:

26024

East Asian (EAS)

AF:

0.728

AC:

28857

AN:

39646

South Asian (SAS)

AF:

0.569

AC:

49040

AN:

86182

European-Finnish (FIN)

AF:

0.512

AC:

27330

AN:

53360

Middle Eastern (MID)

AF:

0.584

AC:

3356

AN:

5746

European-Non Finnish (NFE)

AF:

0.602

AC:

667981

AN:

1109968

Other (OTH)

AF:

0.587

AC:

35351

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

17135

34270

51406

68541

85676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18198

36396

54594

72792

90990

<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:

0.572

AC:

86740

AN:

151618

Hom.:

25038

Cov.:

AF XY:

0.566

AC XY:

41919

AN XY:

74026

show subpopulations

African (AFR)

AF:

0.567

AC:

23421

AN:

41320

American (AMR)

AF:

0.463

AC:

7017

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

1997

AN:

3472

East Asian (EAS)

AF:

0.716

AC:

3672

AN:

5126

South Asian (SAS)

AF:

0.568

AC:

2733

AN:

4812

European-Finnish (FIN)

AF:

0.511

AC:

5386

AN:

10532

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.597

AC:

40528

AN:

67890

Other (OTH)

AF:

0.583

AC:

1222

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1911

3822

5734

7645

9556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.587

Hom.:

79180

Bravo

AF:

0.571

TwinsUK

AF:

0.602

AC:

2231

ALSPAC

AF:

0.611

AC:

2354

ESP6500AA

AF:

0.586

AC:

2194

ESP6500EA

AF:

0.600

AC:

4941

ExAC

AF:

0.579

AC:

69942

Asia WGS

AF:

0.659

AC:

2292

AN:

3476

EpiCase

AF:

0.608

EpiControl

AF:

0.611

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 03, 2021

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

Significance: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

- -

Nov 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2016

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. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Progressive familial intrahepatic cholestasis type 2

Benign:2

Mar 06, 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. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Benign recurrent intrahepatic cholestasis type 2

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2

Benign:1

Jun 28, 2025

Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino"

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

.;T

MetaRNN

Benign

0.000020

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.14

N;N

PhyloP100

2.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.010

N;.

REVEL

Benign

0.26

Sift

Benign

0.25

T;.

Sift4G

Benign

0.59

T;.

Polyphen

0.0010

B;B

Vest4

0.055

MPC

0.17

ClinPred

0.013

GERP RS

4.6

Varity_R

0.10

gMVP

0.68

Mutation Taster

=53/47

polymorphism

(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