rs1521808

Positions:

chr2-168927218-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_003742.4(ABCB11):c.3556G>A(p.Glu1186Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0016 in 1,613,880 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1186G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0087 ( 24 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 16 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Benign; other criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 4.07

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 Benign. Variant got -18 ACMG points.

PM1

In a domain ABC transporter 2 (size 238) in uniprot entity ABCBB_HUMAN there are 32 pathogenic changes around while only 8 benign (80%) in NM_003742.4

BP4

Computational evidence support a benign effect (MetaRNN=0.007329792).

BP6

Variant 2-168927218-C-T is Benign according to our data. Variant chr2-168927218-C-T is described in ClinVar as [Benign, other]. Clinvar id is 195964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00872 (1328/152276) while in subpopulation AFR AF= 0.0303 (1259/41542). AF 95% confidence interval is 0.0289. There are 24 homozygotes in gnomad4. There are 601 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4 linkuse as main transcript	c.3556G>A	p.Glu1186Lys	missense_variant	26/28	ENST00000650372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ABCB11	ENST00000650372.1 linkuse as main transcript	c.3556G>A	p.Glu1186Lys	missense_variant	26/28		NM_003742.4	P1
ABCB11	ENST00000649448.1 linkuse as main transcript	c.1933G>A	p.Glu645Lys	missense_variant	13/15
ABCB11	ENST00000648875.1 linkuse as main transcript	c.19G>A	p.Glu7Lys	missense_variant	1/3
ABCB11	ENST00000439188.1 linkuse as main transcript	c.*1954G>A		3_prime_UTR_variant, NMD_transcript_variant	13/15	2

Frequencies

GnomAD3 genomes

AF:

0.00871

AC:

1325

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00211

AC:

525

AN:

249196

Hom.:

AF XY:

0.00157

AC XY:

212

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.000985

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000856

AC:

1251

AN:

1461604

Hom.:

Cov.:

AF XY:

0.000715

AC XY:

520

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.0317

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00872

AC:

1328

AN:

152276

Hom.:

Cov.:

AF XY:

0.00807

AC XY:

601

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0303

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00157

Hom.:

Bravo

AF:

0.00998

ESP6500AA

AF:

0.0292

AC:

111

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00257

AC:

311

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign; other

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ABCB11: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: ABCB11 c.3556G>A (p.Glu1186Lys) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 249196 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13.86 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCB11 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Progressive familial intrahepatic cholestasis type 2

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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

Benign

0.087

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

.;D;D

MetaRNN

Benign

0.0073

T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.0

D;.;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.014

D;.;.

Sift4G

Benign

0.076

T;.;.

Polyphen

0.88

P;P;.

Vest4

0.12

MVP

0.93

MPC

0.18

ClinPred

0.028

GERP RS

5.7

Varity_R

0.63

gMVP

0.49

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