2-168972025-C-T

Variant names:

• chr2-168972025-C-T
• rs188824058
• NM_003742.4:c.1460G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PM5 PP5_Very_Strong

The NM_003742.4(ABCB11):​c.1460G>A​(p.Arg487His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,612,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004801550: Expression studies in HEK293 cells indicated that whilst the majority of the mutant protein was retained in the ER, the portion of the p.(Arg487His) variant protein which did localize to the cell membrane, retained ABCB11 ATP-dependent transporter activity (Nakano et al. 2019)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 3.42
• Publications: 16 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004801550: Expression studies in HEK293 cells indicated that whilst the majority of the mutant protein was retained in the ER, the portion of the p.(Arg487His) variant protein which did localize to the cell membrane, retained ABCB11 ATP-dependent transporter activity (Nakano et al. 2019).; SCV005907519: "In vitro functional studies provide some evidence that the p.Arg487His variant may slightly impact protein function." PMID:31745229
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_003742.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-168972025-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2070502.
• PP5: Variant 2-168972025-C-T is Pathogenic according to our data. Variant chr2-168972025-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 290081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	NM_003742.4	MANE Select	c.1460G>A	p.Arg487His	missense	Exon 14 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.1460G>A	p.Arg487His	missense	Exon 14 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.1502G>A	p.Arg501His	missense	Exon 14 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.1460G>A	p.Arg487His	missense	Exon 14 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152006 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000928 AC: 23 AN: 247784 AF XY: 0.0000744

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1460544 Hom.: 0 Cov.: 32 AF XY: 0.0000606 AC XY: 44 AN XY: 726556

African (AFR) AF: 0.0000599 AC: 2 AN: 33412

American (AMR) AF: 0.0000449 AC: 2 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000729 AC: 81 AN: 1111224

Other (OTH) AF: 0.000133 AC: 8 AN: 60300

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.000197 AC: 3 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
3	-	-	Progressive familial intrahepatic cholestasis type 2 (3)
2	-	-	Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2 (2)
1	-	-	ABCB11-related disorder (1)
1	-	-	Benign recurrent intrahepatic cholestasis type 2 (1)
1	-	-	Cholestasis, intrahepatic, of pregnancy, 3 (1)
1	-	-	Progressive familial intrahepatic cholestasis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.6	L
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.93
MPC		0.70
ClinPred		0.76	D
GERP RS		5.9
Varity_R		0.79
gMVP		0.85
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs188824058; hg19: chr2-169828535; COSMIC: COSV104562931; COSMIC: COSV104562931;