2-168990819-T-C

Position:

chr2-168990819-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003742.4(ABCB11):c.890A>G(p.Glu297Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.99

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 2-168990819-T-C is Pathogenic according to our data. Variant chr2-168990819-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168990819-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4 linkuse as main transcript	c.890A>G	p.Glu297Gly	missense_variant	9/28	ENST00000650372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1 linkuse as main transcript	c.890A>G	p.Glu297Gly	missense_variant	9/28		NM_003742.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000249

AC:

AN:

248872

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

134992

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000488

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000281

AC:

411

AN:

1460880

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

726722

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000350

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000112

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000306

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2022	Published functional studies demonstrate a damaging effect (severe protein dysfunction) (Wang et al., 2002; Byrne et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18987030, 17855769, 24991443, 19101985, 18395098, 15791618, 20683202, 28776642, 29761168, 28733223, 32581362, 31589614, 34016879, 31319225, 9806540, 12370274) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 297 of the ABCB11 protein (p.Glu297Gly). This variant is present in population databases (rs11568372, gnomAD 0.04%). This missense change has been observed in individuals with progressive familial intrahepatic cholestasis (PMID: 9806540, 19101985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6590). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB11 protein function. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 12370274, 17855769, 19101985). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 01, 2023	PP3, PM2, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ABCB11: PM2, PM3, PP1:Moderate, PP4:Moderate, PS3:Supporting, PS4:Supporting -

Progressive familial intrahepatic cholestasis type 2

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 12, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 03, 2017	- -

Benign recurrent intrahepatic cholestasis type 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

ABCB11-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The ABCB11 c.890A>G variant is predicted to result in the amino acid substitution p.Glu297Gly. This variant has been reported to be pathogenic for intrahepatic cholestasis due to protein misfolding (Strautnieks et al. 1998. PubMed ID: 9806540; Strautnieks et al. 2008. PubMed ID: 18395098; Arnell et al. 2010. PubMed ID: 20683202; Wang et al. 2002. PubMed ID: 12370274). This variant is reported in 0.044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Progressive familial intrahepatic cholestasis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

Across a selection of available literature, the c.890A>G (p.Glu297Gly) variant has been identified in a homozygous state in at least 16 familial intrahepatic cholestasis patients, in a compound heterozygous state in 27 patients, and in a heterozygous state in four patients in whom a second variant was not identified (Strautnieks et al. 1998; Strautnieks et al. 2008; Arnell et al. 2008). The p.Glu297Gly variant was found in a heterozygous state in one of 250 controls and is reported at a frequency of 0.00049 in the European (Non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies demonstrated that the variant destroys a cryptic splice site, leading to approximately 50% of wild type splicing, and disrupts the processing and trafficking of the ABCB11 protein (Hayashi et al. 2005; Byrne et al. 2009). Based on the collective evidence, the p.Glu297Gly variant is classified as pathogenic for familial intrahepatic cholestasis. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.3

D;.

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.94

MPC

0.68

ClinPred

0.81

GERP RS

5.5

Varity_R

0.83

gMVP

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over