rs763782349

Positions:

• chr2-168958011-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_003742.4(ABCB11):​c.2296G>A​(p.Gly766Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,304 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.26

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]

ACMG classification

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, 0.992
• PP5: Variant 2-168958011-C-T is Pathogenic according to our data. Variant chr2-168958011-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 290133.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	c.2296G>A	p.Gly766Arg	missense_variant	19/28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.2296G>A	p.Gly766Arg	missense_variant	19/28		NM_003742.4	ENSP00000497931.1
ABCB11	ENST00000649448.1	c.613G>A	p.Gly205Arg	missense_variant	5/15			ENSP00000497165.1
ABCB11	ENST00000439188.1	n.*766G>A		non_coding_transcript_exon_variant	6/15	2		ENSP00000416058.1
ABCB11	ENST00000439188.1	n.*766G>A		3_prime_UTR_variant	6/15	2		ENSP00000416058.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000283 AC: 7 AN: 247288 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457304 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000166 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 2 Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rolfs Rare Disease Consulting, Rolfs Consulting Und Verwaltungs GmbH	Jan 01, 2021	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 766 of the ABCB11 protein (p.Gly766Arg). This variant is present in population databases (rs763782349, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of progressive familial intrahepatic cholestasis (PMID: 18395098, 21490445, 28733223). This gene is also known as BSEP. ClinVar contains an entry for this variant (Variation ID: 290133). 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCB11 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

ABCB11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2024

The ABCB11 c.2296G>A variant is predicted to result in the amino acid substitution p.Gly766Arg. This variant has been reported in the homozygous, heterozygous, and compound heterozygous state in multiple unrelated patients affected with progressive familial intrahepatic cholestasis (Strautnieks et al. 2008. PubMed ID: 18395098; Evason et al. 2011. PubMed ID: 21490445; Park et al. 2016. PubMed ID: 27239116; Dröge et al. 2017. PubMed ID: 28733223). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Benign recurrent intrahepatic cholestasis type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Progressive familial intrahepatic cholestasis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 30, 2023

Variant summary: ABCB11 c.2296G>A (p.Gly766Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 247288 control chromosomes (gnomAD). c.2296G>A has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (Strautnieks_2008, Evason_2011, Droge_2017, Hertel_2021), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18395098, 21490445, 28733223, 34016879). Three 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.8	H;H;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.2	D;.;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.97		Gain of methylation at G766 (P = 0.0203);Gain of methylation at G766 (P = 0.0203);.;
MVP		0.96
MPC		0.54
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs763782349; hg19: chr2-169814521;