2-168944978-A-G

Variant names:

• chr2-168944978-A-G
• rs853789
• NM_003742.4:c.2344-17T>C

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.2344-17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 1,468,048 control chromosomes in the GnomAD database, including 361,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44667 hom., cov: 31)
  • Exomes 𝑓: 0.69 (316482 hom.)
• Consequence: ABCB11 NM_003742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.147
• Publications: 23 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=-0.84).
• BP6: Variant 2-168944978-A-G is Benign according to our data. Variant chr2-168944978-A-G is described in ClinVar as Benign. ClinVar VariationId is 259148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.2344-17T>C		intron_variant	Intron 19 of 27	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.2344-17T>C		intron_variant	Intron 19 of 27		NM_003742.4	ENSP00000497931.1
ABCB11	ENST00000649448.1	c.661-17T>C		intron_variant	Intron 5 of 14			ENSP00000497165.1
ABCB11	ENST00000439188.1	n.*814-17T>C		intron_variant	Intron 6 of 14	2		ENSP00000416058.1

Frequencies

GnomAD3 genomes AF: 0.758 AC: 114980 AN: 151714 Hom.: 44606 Cov.: 31

Gnomad AFR AF: 0.900

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.986

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.753

GnomAD2 exomes AF: 0.753 AC: 101832 AN: 135242 AF XY: 0.751

Gnomad AFR exome AF: 0.908

Gnomad AMR exome AF: 0.840

Gnomad ASJ exome AF: 0.760

Gnomad EAS exome AF: 0.988

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.726

GnomAD4 exome AF: 0.689 AC: 906734 AN: 1316216 Hom.: 316482 Cov.: 20 AF XY: 0.692 AC XY: 450345 AN XY: 651196

African (AFR) AF: 0.912 AC: 26071 AN: 28582

American (AMR) AF: 0.833 AC: 23545 AN: 28262

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 17809 AN: 23402

East Asian (EAS) AF: 0.990 AC: 34952 AN: 35300

South Asian (SAS) AF: 0.835 AC: 59302 AN: 71062

European-Finnish (FIN) AF: 0.663 AC: 32297 AN: 48690

Middle Eastern (MID) AF: 0.736 AC: 3471 AN: 4716

European-Non Finnish (NFE) AF: 0.655 AC: 669465 AN: 1021318

Other (OTH) AF: 0.726 AC: 39822 AN: 54884

GnomAD4 genome AF: 0.758 AC: 115104 AN: 151832 Hom.: 44667 Cov.: 31 AF XY: 0.763 AC XY: 56584 AN XY: 74194

African (AFR) AF: 0.900 AC: 37315 AN: 41442

American (AMR) AF: 0.786 AC: 11992 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 2587 AN: 3466

East Asian (EAS) AF: 0.986 AC: 5044 AN: 5114

South Asian (SAS) AF: 0.845 AC: 4071 AN: 4820

European-Finnish (FIN) AF: 0.672 AC: 7100 AN: 10562

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44490 AN: 67862

Other (OTH) AF: 0.753 AC: 1589 AN: 2110

Alfa AF: 0.778 Hom.: 17800

Bravo AF: 0.774

Asia WGS AF: 0.908 AC: 3155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

-

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

- -

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

- -

Progressive familial 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	-0.84
CADD	Benign	0.33
DANN	Benign	0.77
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs853789; hg19: chr2-169801488;