NM_003742.4:c.2029A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003742.4(ABCB11):c.2029A>G(p.Met677Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,611,012 control chromosomes in the GnomAD database, including 1,425 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 626 hom., cov: 32)

Exomes 𝑓: 0.020 ( 799 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0370

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

progressive familial intrahepatic cholestasis type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
benign recurrent intrahepatic cholestasis type 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ABCB11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014809668).

BP6

Variant 2-168968473-T-C is Benign according to our data. Variant chr2-168968473-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.2029A>G	p.Met677Val	missense_variant	Exon 17 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.2029A>G	p.Met677Val	missense_variant	Exon 17 of 28		NM_003742.4	ENSP00000497931.1	O95342
ABCB11	ENST00000649448.1 link	c.346A>G	p.Met116Val	missense_variant	Exon 3 of 15			ENSP00000497165.1	A0A3B3IS78
ABCB11	ENST00000439188.1 link	n.*499A>G		non_coding_transcript_exon_variant	Exon 4 of 15	2		ENSP00000416058.1	H7C486
ABCB11	ENST00000439188.1 link	n.*499A>G		3_prime_UTR_variant	Exon 4 of 15	2		ENSP00000416058.1	H7C486

Frequencies

GnomAD3 genomes

AF:

0.0579

AC:

8790

AN:

151902

Hom.:

623

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0326

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0521

GnomAD2 exomes

AF:

0.0236

AC:

5830

AN:

246646

AF XY:

0.0213

show subpopulations

Gnomad AFR exome

AF:

0.170

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00313

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0199

AC:

29026

AN:

1458992

Hom.:

799

Cov.:

AF XY:

0.0192

AC XY:

13917

AN XY:

725688

show subpopulations

African (AFR)

AF:

0.179

AC:

5978

AN:

33352

American (AMR)

AF:

0.0182

AC:

810

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

359

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39518

South Asian (SAS)

AF:

0.0119

AC:

1021

AN:

85944

European-Finnish (FIN)

AF:

0.00345

AC:

184

AN:

53274

Middle Eastern (MID)

AF:

0.0445

AC:

256

AN:

5752

European-Non Finnish (NFE)

AF:

0.0170

AC:

18833

AN:

1110394

Other (OTH)

AF:

0.0263

AC:

1585

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1246

2491

3737

4982

6228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

796

1592

2388

3184

3980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0579

AC:

8808

AN:

152020

Hom.:

626

Cov.:

AF XY:

0.0556

AC XY:

4133

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.164

AC:

6818

AN:

41504

American (AMR)

AF:

0.0325

AC:

495

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.0108

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1237

AN:

67904

Other (OTH)

AF:

0.0520

AC:

110

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

378

756

1135

1513

1891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0304

Hom.:

571

Bravo

AF:

0.0643

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.163

AC:

618

ESP6500EA

AF:

0.0200

AC:

165

ExAC

AF:

0.0266

AC:

3216

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0211

EpiControl

AF:

0.0214

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 09, 2016

GeneDx

Significance: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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Progressive familial intrahepatic cholestasis type 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.35

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.38

.;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.065

N;N;.

PhyloP100

0.037

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.49

N;.;.

REVEL

Benign

0.21

Sift

Benign

0.28

T;.;.

Sift4G

Benign

0.61

T;.;.

Polyphen

0.0

B;B;.

Vest4

0.010

MPC

0.14

ClinPred

0.0025

GERP RS

-2.0

Varity_R

0.092

gMVP

0.29

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -46

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over