Genetic Variant ABCB11:p.Arg432Lys (chr2-168976590-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_003742.4(ABCB11):c.1295G>A(p.Arg432Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R432T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-168976590-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6595.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.1295G>A	p.Arg432Lys	missense_variant	Exon 12 of 28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1 link	c.1295G>A	p.Arg432Lys	missense_variant	Exon 12 of 28		NM_003742.4	ENSP00000497931.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33106

American (AMR)

AF:

0.00

AC:

AN:

44152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

85162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098692

Other (OTH)

AF:

0.00

AC:

AN:

59750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.56

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

1.6

L;L

PhyloP100

7.9

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.6

D;.

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Vest4

0.65

ClinPred

0.99

GERP RS

5.7

Varity_R

0.75

gMVP

0.90

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over