2-168968498-A-C

Position:

chr2-168968498-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_003742.4(ABCB11):c.2012-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,607,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

ABCB11
NM_003742.4 splice_region, intron

Scores

Splicing: ADA: 0.9881

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.19

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-168968498-A-C is Pathogenic according to our data. Variant chr2-168968498-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4 linkuse as main transcript	c.2012-8T>G		splice_region_variant, intron_variant		ENST00000650372.1	NP_003733.2	O95342

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
ABCB11	ENST00000650372.1 linkuse as main transcript	c.2012-8T>G	splice_region_variant, intron_variant		NM_003742.4	ENSP00000497931.1	O95342
ABCB11	ENST00000649448.1 linkuse as main transcript	c.329-8T>G	splice_region_variant, intron_variant			ENSP00000497165.1	A0A3B3IS78
ABCB11	ENST00000439188.1 linkuse as main transcript	n.*482-8T>G	splice_region_variant, intron_variant	2		ENSP00000416058.1	H7C486

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000245

AC:

AN:

244560

Hom.:

AF XY:

0.0000377

AC XY:

AN XY:

132542

show subpopulations

Gnomad AFR exome

AF:

0.0000656

Gnomad AMR exome

AF:

0.00

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:

0.0000452

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000865

AC:

126

AN:

1455902

Hom.:

Cov.:

AF XY:

0.0000857

AC XY:

AN XY:

723702

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:

0.00

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2023	Non-canonical splice site variant demonstrated to result in loss of function (Strautnieks et al., 2008); This variant is associated with the following publications: (PMID: 16871584, 32581362, 35894240, 24402531, 20583290, 24231640, 18395098) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change falls in intron 16 of the ABCB11 gene. It does not directly change the encoded amino acid sequence of the ABCB11 protein. This variant is present in population databases (rs769910565, gnomAD 0.006%). This variant has been observed in individuals with ABCB11-related conditions (PMID: 18395098). ClinVar contains an entry for this variant (Variation ID: 284637). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Progressive familial intrahepatic cholestasis type 2

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	The ABCB11 c.2012-8T>G variant has been identified in a compound heterozygous state in at least six probands and in a heterozygous state in one proband in whom a second variant was not identified, all with familial intrahepatic cholestasis (Knisely et al. 2006; Siebold et al. 2010; Strautnieks et al. 2008; Grammatikopoulos et al. 2015). The c.2012-8T>G variant was absent from 500 control individuals and is reported at a frequency of 0.000056 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the c.2012-8T>G variant is classified as likely pathogenic for familial intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

ABCB11-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2023

The ABCB11 c.2012-8T>G variant is predicted to interfere with splicing. This variant was previously reported in the compound heterozygous state in individuals who presented with familial intrahepatic cholestasis (Knisely et al. 2006. PubMed ID: 16871584, reported as IVS16-8T>G; Siebold et al. 2010. PubMed ID: 20583290; Strautnieks et al. 2008. PubMed ID: 18395098). In vitro analysis from one study indicated that this variant led to skipping of exon 17 and a resulting frameshift with premature protein termination (Knisely et al. 2006. PubMed ID: 16871584). This variant is reported in 0.0056% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-169825008-A-C) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/284637/). This variant is interpreted as pathogenic. -

Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Benign recurrent intrahepatic cholestasis type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 12, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Progressive familial intrahepatic cholestasis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 11, 2023

Variant summary: ABCB11 c.2012-8T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3' cryptic acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.5e-05 in 244560 control chromosomes. c.2012-8T>G has been reported in the literature at a compound heterozygous state along with difference pathogenic variants in multiple individuals affected with Familial Intrahepatic Cholestasis (examples, Knisely_2006, Strautnieks_2008). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on splicing, however, detailed information of such results are not available for an independent evaluation (Strautnieks_2008). The following publications have been ascertained in the context of this evaluation (PMID: 16871584, 18395098). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

9.7

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.38

Position offset: -8

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