rs2287618

Variant names:

• chr2-168986299-T-C
• rs2287618
• NM_003742.4:c.909-15A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003742.4(ABCB11):​c.909-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,607,150 control chromosomes in the GnomAD database, including 397,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40774 hom., cov: 32)
  • Exomes 𝑓: 0.70 (357173 hom.)
• Consequence: ABCB11 NM_003742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.61
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-168986299-T-C is Benign according to our data. Variant chr2-168986299-T-C is described in ClinVar as Benign. ClinVar VariationId is 259158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.909-15A>G		intron_variant	Intron 9 of 27	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.909-15A>G		intron_variant	Intron 9 of 27		NM_003742.4	ENSP00000497931.1

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110510 AN: 151934 Hom.: 40732 Cov.: 32

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.726

GnomAD2 exomes AF: 0.695 AC: 172088 AN: 247692 AF XY: 0.702

Gnomad AFR exome AF: 0.828

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.810

Gnomad FIN exome AF: 0.711

Gnomad NFE exome AF: 0.694

Gnomad OTH exome AF: 0.681

GnomAD4 exome AF: 0.698 AC: 1016246 AN: 1455098 Hom.: 357173 Cov.: 33 AF XY: 0.700 AC XY: 507241 AN XY: 724132

African (AFR) AF: 0.836 AC: 27728 AN: 33164

American (AMR) AF: 0.507 AC: 22589 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 18780 AN: 26056

East Asian (EAS) AF: 0.805 AC: 31896 AN: 39644

South Asian (SAS) AF: 0.758 AC: 65149 AN: 85990

European-Finnish (FIN) AF: 0.699 AC: 37248 AN: 53258

Middle Eastern (MID) AF: 0.686 AC: 3152 AN: 4594

European-Non Finnish (NFE) AF: 0.692 AC: 767010 AN: 1107794

Other (OTH) AF: 0.711 AC: 42694 AN: 60038

GnomAD4 genome AF: 0.727 AC: 110613 AN: 152052 Hom.: 40774 Cov.: 32 AF XY: 0.727 AC XY: 54031 AN XY: 74316

African (AFR) AF: 0.830 AC: 34428 AN: 41498

American (AMR) AF: 0.582 AC: 8882 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2512 AN: 3468

East Asian (EAS) AF: 0.811 AC: 4184 AN: 5160

South Asian (SAS) AF: 0.766 AC: 3690 AN: 4816

European-Finnish (FIN) AF: 0.717 AC: 7576 AN: 10564

Middle Eastern (MID) AF: 0.668 AC: 195 AN: 292

European-Non Finnish (NFE) AF: 0.691 AC: 46989 AN: 67980

Other (OTH) AF: 0.730 AC: 1541 AN: 2112

Alfa AF: 0.698 Hom.: 68834

Bravo AF: 0.720

Asia WGS AF: 0.823 AC: 2864 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 02, 2015

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign recurrent intrahepatic cholestasis type 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.033
DANN	Benign	0.31
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2287618; hg19: chr2-169842809;