2-169014372-A-G

Variant names:

• chr2-169014372-A-G
• rs4148776
• NM_003742.4:c.99-18T>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.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
• Publications: 8 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=-0.73).
• BP6: Variant 2-169014372-A-G is Benign according to our data. Variant chr2-169014372-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.99-18T>C		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.99-18T>C		intron	N/A	ENSP00000497931.1
	ABCB11	ENST00000858973.1		c.141-18T>C		intron	N/A	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.99-18T>C		intron	N/A	ENSP00000529031.1

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

GnomAD2 exomes AF: 0.0781 AC: 19374 AN: 248216 AF XY: 0.0743

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 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

African (AFR) AF: 0.309 AC: 10291 AN: 33284

American (AMR) AF: 0.0511 AC: 2280 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2616 AN: 26076

East Asian (EAS) AF: 0.0637 AC: 2523 AN: 39614

South Asian (SAS) AF: 0.0627 AC: 5401 AN: 86080

European-Finnish (FIN) AF: 0.102 AC: 5405 AN: 53176

Middle Eastern (MID) AF: 0.0709 AC: 408 AN: 5754

European-Non Finnish (NFE) AF: 0.0539 AC: 59721 AN: 1108996

Other (OTH) AF: 0.0787 AC: 4740 AN: 60224

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

African (AFR) AF: 0.303 AC: 12572 AN: 41428

American (AMR) AF: 0.0760 AC: 1160 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 351 AN: 3470

East Asian (EAS) AF: 0.0620 AC: 321 AN: 5176

South Asian (SAS) AF: 0.0690 AC: 333 AN: 4826

European-Finnish (FIN) AF: 0.110 AC: 1169 AN: 10610

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0558 AC: 3793 AN: 67996

Other (OTH) AF: 0.102 AC: 216 AN: 2114

Alfa AF: 0.0754 Hom.: 1467

Bravo AF: 0.137

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (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	-0.73
CADD	Benign	2.7
DANN	Benign	0.82
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4148776; hg19: chr2-169870882;