rs118109635

Variant names:

Variant summary

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

The NM_003742.4(ABCB11):c.2594C>T(p.Ala865Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,605,336 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A865T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 4 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 10.0

Publications

23 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=0.010960311).

BP6

Variant 2-168944621-G-A is Benign according to our data. Variant chr2-168944621-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00048 (73/152092) while in subpopulation EAS AF = 0.013 (67/5148). AF 95% confidence interval is 0.0105. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.2594C>T	p.Ala865Val	missense_variant	Exon 21 of 28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCB11	ENST00000650372.1 link	c.2594C>T	p.Ala865Val	missense_variant	Exon 21 of 28		NM_003742.4	ENSP00000497931.1
ABCB11	ENST00000649448.1 link	c.911C>T	p.Ala304Val	missense_variant	Exon 7 of 15			ENSP00000497165.1
ABCB11	ENST00000439188.1 link	n.*1064C>T		non_coding_transcript_exon_variant	Exon 8 of 15	2		ENSP00000416058.1
ABCB11	ENST00000439188.1 link	n.*1064C>T		3_prime_UTR_variant	Exon 8 of 15	2		ENSP00000416058.1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0130

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00114

AC:

277

AN:

243644

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000403

AC:

586

AN:

1453244

Hom.:

Cov.:

AF XY:

0.000475

AC XY:

343

AN XY:

721902

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33148

American (AMR)

AF:

0.0000228

AC:

AN:

43836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25798

East Asian (EAS)

AF:

0.0111

AC:

440

AN:

39560

South Asian (SAS)

AF:

0.00127

AC:

108

AN:

84860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.000525

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1107094

Other (OTH)

AF:

0.000350

AC:

AN:

59978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000480

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.0130

AC:

AN:

5148

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67946

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

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:

0.000590

Hom.:

Bravo

AF:

0.000684

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCB11: BS1 -

not specified

Benign:2

Sep 25, 2017

GeneDx

Significance:Likely 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. -

Aug 25, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCB11-related disorder

Benign:1

Mar 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Progressive familial intrahepatic cholestasis type 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;D;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.9

L;L;.

PhyloP100

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.4

D;.;.

REVEL

Uncertain

0.55

Sift

Benign

0.082

T;.;.

Sift4G

Benign

0.083

T;.;.

Polyphen

0.88

P;P;.

Vest4

0.83

MVP

0.94

MPC

0.39

ClinPred

0.14

GERP RS

5.7

Varity_R

0.56

gMVP

0.85

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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