chr2-168944621-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003742.4(ABCB11):c.2594C>T(p.Ala865Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,605,336 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 4 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 10.0

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010960311).

BP6

Variant 2-168944621-G-A is Benign according to our data. Variant chr2-168944621-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168944621-G-A is described in Lovd as [Benign]. Variant chr2-168944621-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00048 (73/152092) while in subpopulation EAS AF= 0.013 (67/5148). AF 95% confidence interval is 0.0105. There are 1 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.2594C>T	p.Ala865Val	missense_variant	Exon 21 of 28	ENST00000650372.1	NP_003733.2	O95342

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCB11	ENST00000650372.1 link	c.2594C>T	p.Ala865Val	missense_variant	Exon 21 of 28		NM_003742.4	ENSP00000497931.1	O95342
ABCB11	ENST00000649448.1 link	c.911C>T	p.Ala304Val	missense_variant	Exon 7 of 15			ENSP00000497165.1	A0A3B3IS78
ABCB11	ENST00000439188.1 link	n.*1064C>T		non_coding_transcript_exon_variant	Exon 8 of 15	2		ENSP00000416058.1	H7C486
ABCB11	ENST00000439188.1 link	n.*1064C>T		3_prime_UTR_variant	Exon 8 of 15	2		ENSP00000416058.1	H7C486

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0130

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00114

AC:

277

AN:

243644

Hom.:

AF XY:

0.00114

AC XY:

150

AN XY:

132062

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0138

Gnomad SAS exome

AF:

0.000959

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000403

AC:

586

AN:

1453244

Hom.:

Cov.:

AF XY:

0.000475

AC XY:

343

AN XY:

721902

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0111

Gnomad4 SAS exome

AF:

0.00127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000350

GnomAD4 genome

AF:

0.000480

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0130

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000825

Hom.:

Bravo

AF:

0.000684

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCB11: BS1 -

Mar 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Sep 25, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 25, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCB11-related disorder

Benign:1

Mar 14, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Progressive familial intrahepatic cholestasis type 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Uncertain

0.38

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;D;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.9

L;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.4

D;.;.

REVEL

Uncertain

0.55

Sift

Benign

0.082

T;.;.

Sift4G

Benign

0.083

T;.;.

Polyphen

0.88

P;P;.

Vest4

0.83

MVP

0.94

MPC

0.39

ClinPred

0.14

GERP RS

5.7

Varity_R

0.56

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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