rs4148776

Positions:

• chr2-169014372-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003742.4(ABCB11):​c.99-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 1,609,928 control chromosomes in the GnomAD database, including 6,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2213 hom., cov: 32)
  • Exomes 𝑓: 0.064 (4270 hom.)
• Consequence: ABCB11 NM_003742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.577

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-169014372-A-G is Benign according to our data. Variant chr2-169014372-A-G is described in ClinVar as [Benign]. Clinvar id is 259160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4	c.99-18T>C		intron_variant		ENST00000650372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.99-18T>C		intron_variant			NM_003742.4	P1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19881 AN: 151980 Hom.: 2198 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0761

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0617

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.0781 AC: 19374 AN: 248216 Hom.: 1284 AF XY: 0.0743 AC XY: 10006 AN XY: 134668

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0593

Gnomad SAS exome AF: 0.0604

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0554

Gnomad OTH exome AF: 0.0710

GnomAD4 exome AF: 0.0641 AC: 93385 AN: 1457830 Hom.: 4270 Cov.: 30 AF XY: 0.0633 AC XY: 45890 AN XY: 725478

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.0511

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.0637

Gnomad4 SAS exome AF: 0.0627

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0539

Gnomad4 OTH exome AF: 0.0787

GnomAD4 genome AF: 0.131 AC: 19936 AN: 152098 Hom.: 2213 Cov.: 32 AF XY: 0.130 AC XY: 9680 AN XY: 74392

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.0760

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.0620

Gnomad4 SAS AF: 0.0690

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0558

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0680 Hom.: 833

Bravo AF: 0.137

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Benign recurrent intrahepatic cholestasis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Progressive familial intrahepatic cholestasis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.7
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4148776; hg19: chr2-169870882;