chr2-168973818-A-G

Position:

chr2-168973818-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003742.4(ABCB11):c.1331T>C(p.Val444Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,610,750 control chromosomes in the GnomAD database, including 282,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V444D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.57 ( 25038 hom., cov: 30)

Exomes 𝑓: 0.59 ( 257725 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.39

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.0099598E-5).

BP6

Variant 2-168973818-A-G is Benign according to our data. Variant chr2-168973818-A-G is described in ClinVar as [Benign]. Clinvar id is 194214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168973818-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4 linkuse as main transcript	c.1331T>C	p.Val444Ala	missense_variant	13/28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1 linkuse as main transcript	c.1331T>C	p.Val444Ala	missense_variant	13/28		NM_003742.4	ENSP00000497931	P1

Frequencies

GnomAD3 genomes

AF:

0.572

AC:

86689

AN:

151500

Hom.:

25023

Cov.:

show subpopulations

Gnomad AFR

AF:

0.567

Gnomad AMI

AF:

0.660

Gnomad AMR

AF:

0.463

Gnomad ASJ

AF:

0.575

Gnomad EAS

AF:

0.717

Gnomad SAS

AF:

0.567

Gnomad FIN

AF:

0.511

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.597

Gnomad OTH

AF:

0.580

GnomAD3 exomes

AF:

0.569

AC:

141494

AN:

248542

Hom.:

41134

AF XY:

0.574

AC XY:

77402

AN XY:

134806

show subpopulations

Gnomad AFR exome

AF:

0.571

Gnomad AMR exome

AF:

0.423

Gnomad ASJ exome

AF:

0.558

Gnomad EAS exome

AF:

0.728

Gnomad SAS exome

AF:

0.576

Gnomad FIN exome

AF:

0.515

Gnomad NFE exome

AF:

0.599

Gnomad OTH exome

AF:

0.564

GnomAD4 exome

AF:

0.593

AC:

864780

AN:

1459132

Hom.:

257725

Cov.:

AF XY:

0.592

AC XY:

429695

AN XY:

725906

show subpopulations

Gnomad4 AFR exome

AF:

0.578

Gnomad4 AMR exome

AF:

0.424

Gnomad4 ASJ exome

AF:

0.563

Gnomad4 EAS exome

AF:

0.728

Gnomad4 SAS exome

AF:

0.569

Gnomad4 FIN exome

AF:

0.512

Gnomad4 NFE exome

AF:

0.602

Gnomad4 OTH exome

AF:

0.587

GnomAD4 genome

AF:

0.572

AC:

86740

AN:

151618

Hom.:

25038

Cov.:

AF XY:

0.566

AC XY:

41919

AN XY:

74026

show subpopulations

Gnomad4 AFR

AF:

0.567

Gnomad4 AMR

AF:

0.463

Gnomad4 ASJ

AF:

0.575

Gnomad4 EAS

AF:

0.716

Gnomad4 SAS

AF:

0.568

Gnomad4 FIN

AF:

0.511

Gnomad4 NFE

AF:

0.597

Gnomad4 OTH

AF:

0.583

Alfa

AF:

0.598

Hom.:

53383

Bravo

AF:

0.571

TwinsUK

AF:

0.602

AC:

2231

ALSPAC

AF:

0.611

AC:

2354

ESP6500AA

AF:

0.586

AC:

2194

ESP6500EA

AF:

0.600

AC:

4941

ExAC

AF:

0.579

AC:

69942

Asia WGS

AF:

0.659

AC:

2292

AN:

3476

EpiCase

AF:

0.608

EpiControl

AF:

0.611

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
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	Dec 03, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Progressive familial intrahepatic cholestasis type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Benign recurrent intrahepatic cholestasis type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

.;T

MetaRNN

Benign

0.000020

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.14

N;N

MutationTaster

Benign

0.076

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.010

N;.

REVEL

Benign

0.26

Sift

Benign

0.25

T;.

Sift4G

Benign

0.59

T;.

Polyphen

0.0010

B;B

Vest4

0.055

MPC

0.17

ClinPred

0.013

GERP RS

4.6

Varity_R

0.10

gMVP

0.68

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