2-168944978-A-G

Position:

• chr2-168944978-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.2344-17T>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.147

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=-0.84).
• BP6: Variant 2-168944978-A-G is Benign according to our data. Variant chr2-168944978-A-G is described in ClinVar as [Benign]. Clinvar id is 259148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168944978-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.2344-17T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.2344-17T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_003742.4	ENSP00000497931	P1
ABCB11	ENST00000649448.1	c.661-17T>C		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000497165
ABCB11	ENST00000439188.1	c.*814-17T>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000416058

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

GnomAD3 exomes AF: 0.753 AC: 101832 AN: 135242 Hom.: 39100 AF XY: 0.751 AC XY: 53352 AN XY: 71008

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 SAS exome AF: 0.834

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

Gnomad4 AFR exome AF: 0.912

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.761

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.835

Gnomad4 FIN exome AF: 0.663

Gnomad4 NFE exome AF: 0.655

Gnomad4 OTH exome AF: 0.726

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

Gnomad4 AFR AF: 0.900

Gnomad4 AMR AF: 0.786

Gnomad4 ASJ AF: 0.746

Gnomad4 EAS AF: 0.986

Gnomad4 SAS AF: 0.845

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.656

Gnomad4 OTH AF: 0.753

Alfa AF: 0.735 Hom.: 10732

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

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

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	-0.84
CADD	Benign	0.33
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs853789; hg19: chr2-169801488;