rs11568372

Variant names:

• chr2-168990819-T-C
• rs11568372
• NM_003742.4:c.890A>G
• ABCB11 p.Glu297Gly

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_003742.4(ABCB11):​c.890A>G​(p.Glu297Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000418972: "In vitro functional studies demonstrated that the variant destroys a cryptic splice site, leading to approximately 50% of wild type splicing, and disrupts the processing and trafficking of the ABCB11 protein (Hayashi et al. 2005" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E297K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 7.99
• Publications: 76 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, Labcorp Genetics (formerly Invitae), Orphanet
• benign recurrent intrahepatic cholestasis type 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000418972: "In vitro functional studies demonstrated that the variant destroys a cryptic splice site, leading to approximately 50% of wild type splicing, and disrupts the processing and trafficking of the ABCB11 protein (Hayashi et al. 2005; Byrne et al. 2009)."; SCV000958550: Experimental studies have shown that this missense change affects ABCB11 function (PMID: 12370274, 17855769, 19101985).; SCV002064161: Published functional studies demonstrate a damaging effect (severe protein dysfunction) (Wang et al., 2002; Byrne et al., 2009); SCV004723550: This variant has been reported to be pathogenic for intrahepatic cholestasis due to protein misfolding (Strautnieks et al. 1998. PubMed ID: 9806540; Strautnieks et al. 2008. PubMed ID: 18395098; Arnell et al. 2010. PubMed ID: 20683202; Wang et al. 2002. PubMed ID: 12370274).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 2-168990819-T-C is Pathogenic according to our data. Variant chr2-168990819-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6590.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.890A>G	p.Glu297Gly	missense	Exon 9 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.890A>G	p.Glu297Gly	missense	Exon 9 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.932A>G	p.Glu311Gly	missense	Exon 9 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.890A>G	p.Glu297Gly	missense	Exon 9 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000249 AC: 62 AN: 248872 AF XY: 0.000237

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000488

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000281 AC: 411 AN: 1460880 Hom.: 0 Cov.: 31 AF XY: 0.000274 AC XY: 199 AN XY: 726722

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000350 AC: 389 AN: 1111322

Other (OTH) AF: 0.000298 AC: 18 AN: 60308

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74314

African (AFR) AF: 0.000121 AC: 5 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68016

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000290 Hom.: 2

Bravo AF: 0.000140

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	not provided (10)
3	-	-	Progressive familial intrahepatic cholestasis type 2 (3)
2	-	-	Benign recurrent intrahepatic cholestasis type 2 (2)
1	-	-	ABCB11-related disorder (1)
1	-	-	Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.83
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11568372;

hg19: chr2-169847329;