2-168968498-A-G

Variant names:

• chr2-168968498-A-G
• rs769910565
• NM_003742.4:c.2012-8T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000650372.1(ABCB11):​c.2012-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCB11 ENST00000650372.1 splice_region, intron
• Scores: Splicing: ADA: 0.006535
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.19
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000650372.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	NM_003742.4	MANE Select	c.2012-8T>C		splice_region intron	N/A	NP_003733.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.2012-8T>C		splice_region intron	N/A	ENSP00000497931.1
	ABCB11	ENST00000649448.1		c.329-8T>C		splice_region intron	N/A	ENSP00000497165.1
	ABCB11	ENST00000439188.1	TSL:2	n.*482-8T>C		splice_region intron	N/A	ENSP00000416058.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455904 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723702

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00 AC: 0 AN: 85630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108302

Other (OTH) AF: 0.00 AC: 0 AN: 60082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Progressive familial intrahepatic cholestasis type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.63
PhyloP100		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0065
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -8

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

Other links and lift over

dbSNP: rs769910565; hg19: chr2-169825008;