rs748716950

Variant names:

• chr2-168972057-AGCATGG-A
• rs748716950
• NM_003742.4:c.1435-13_1435-8delCCATGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_003742.4(ABCB11):​c.1435-13_1435-8delCCATGC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,611,340 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: ABCB11 NM_003742.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.947
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-168972057-AGCATGG-A is Benign according to our data. Variant chr2-168972057-AGCATGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402331.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.1435-13_1435-8delCCATGC		splice_region_variant, intron_variant	Intron 13 of 27	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.1435-13_1435-8delCCATGC		splice_region_variant, intron_variant	Intron 13 of 27		NM_003742.4	ENSP00000497931.1
ABCB11	ENST00000439188.1	n.-31_-26delCCATGC		upstream_gene_variant		2		ENSP00000416058.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000191 AC: 47 AN: 246012 AF XY: 0.000180

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000303 AC: 442 AN: 1459300 Hom.: 1 AF XY: 0.000277 AC XY: 201 AN XY: 725878

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.0000450 AC: 2 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000382 AC: 424 AN: 1110438

Other (OTH) AF: 0.000249 AC: 15 AN: 60252

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74264

African (AFR) AF: 0.0000724 AC: 3 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15226

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67994

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

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000193

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF in gene is associated with intrahepatic cholestasis. Unclear whether it would impact splicing. Reported in one patient who had a second variant in the gene. -

Apr 16, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCB11 c.1435-13_1435-8delCCATGC alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00019 in 246012 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCB11 causing Familial Intrahepatic Cholestasis (0.00019 vs 0.0022), allowing no conclusion about variant significance. c.1435-13_1435-8delCCATGC has been observed in at least one individual affected with Familial Intrahepatic Cholestasis (Knisely_2006, Strautnieks_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 402331). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1 Benign:1

Feb 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 2 Uncertain:1

Feb 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95
Mutation Taster		=39/61	disease causing

Splicing

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

Other links and lift over

dbSNP: rs748716950; hg19: chr2-169828567; COSMIC: COSV108751851;