2-168973645-G-A

Variant names:

• chr2-168973645-G-A
• rs2287623
• NM_003742.4:c.1434+70C>T

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.1434+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,556,316 control chromosomes in the GnomAD database, including 274,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25203 hom., cov: 31)
  • Exomes 𝑓: 0.59 (248905 hom.)
• Consequence: ABCB11 NM_003742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0960
• Publications: 53 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=-0.87).
• BP6: Variant 2-168973645-G-A is Benign according to our data. Variant chr2-168973645-G-A is described in ClinVar as Benign. ClinVar VariationId is 1184648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	NM_003742.4	MANE Select	c.1434+70C>T		intron	N/A	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.1434+70C>T		intron	N/A	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.1476+70C>T		intron	N/A	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.1434+70C>T		intron	N/A	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86941 AN: 151612 Hom.: 25189 Cov.: 31

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.580

GnomAD4 exome AF: 0.593 AC: 833197 AN: 1404586 Hom.: 248905 AF XY: 0.592 AC XY: 412344 AN XY: 695948

African (AFR) AF: 0.578 AC: 18573 AN: 32156

American (AMR) AF: 0.421 AC: 17858 AN: 42408

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 13420 AN: 23900

East Asian (EAS) AF: 0.752 AC: 29045 AN: 38630

South Asian (SAS) AF: 0.567 AC: 46067 AN: 81210

European-Finnish (FIN) AF: 0.511 AC: 26503 AN: 51818

Middle Eastern (MID) AF: 0.584 AC: 3217 AN: 5508

European-Non Finnish (NFE) AF: 0.602 AC: 644494 AN: 1071178

Other (OTH) AF: 0.589 AC: 34020 AN: 57778

GnomAD4 genome AF: 0.573 AC: 86991 AN: 151730 Hom.: 25203 Cov.: 31 AF XY: 0.568 AC XY: 42068 AN XY: 74120

African (AFR) AF: 0.567 AC: 23466 AN: 41392

American (AMR) AF: 0.463 AC: 7029 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1994 AN: 3468

East Asian (EAS) AF: 0.749 AC: 3840 AN: 5124

South Asian (SAS) AF: 0.569 AC: 2740 AN: 4818

European-Finnish (FIN) AF: 0.513 AC: 5400 AN: 10534

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40529 AN: 67900

Other (OTH) AF: 0.583 AC: 1227 AN: 2104

Alfa AF: 0.590 Hom.: 90559

Bravo AF: 0.572

Asia WGS AF: 0.670 AC: 2330 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.42
PhyloP100		-0.096
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2287623; hg19: chr2-169830155; COSMIC: COSV55597948; COSMIC: COSV55597948;