rs11568363

Variant names:

• chr2-169013264-C-T
• rs11568363
• NM_003742.4:c.389+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-169013264-C-T
• chr2-169013264-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003742.4(ABCB11):​c.389+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,583,062 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (68 hom., cov: 32)
  • Exomes 𝑓: 0.018 (289 hom.)
• Consequence: ABCB11 NM_003742.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003654
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0410
• Publications: 3 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=-0.77).
• BP6: Variant 2-169013264-C-T is Benign according to our data. Variant chr2-169013264-C-T is described in ClinVar as Benign. ClinVar VariationId is 259154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0234 (3567/152164) while in subpopulation AFR AF = 0.0407 (1690/41508). AF 95% confidence interval is 0.0391. There are 68 homozygotes in GnomAd4. There are 1678 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 AR gene

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.389+8G>A		splice_region 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.389+8G>A		splice_region intron	N/A	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.431+8G>A		splice_region intron	N/A	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.389+8G>A		splice_region intron	N/A	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3567 AN: 152046 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0162 AC: 3788 AN: 234224 AF XY: 0.0164

Gnomad AFR exome AF: 0.0387

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0177 AC: 25302 AN: 1430898 Hom.: 289 Cov.: 29 AF XY: 0.0176 AC XY: 12504 AN XY: 709372

African (AFR) AF: 0.0433 AC: 1385 AN: 32014

American (AMR) AF: 0.0136 AC: 548 AN: 40298

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 638 AN: 25108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39290

South Asian (SAS) AF: 0.0127 AC: 1036 AN: 81644

European-Finnish (FIN) AF: 0.00397 AC: 210 AN: 52936

Middle Eastern (MID) AF: 0.0345 AC: 194 AN: 5616

European-Non Finnish (NFE) AF: 0.0184 AC: 20201 AN: 1094988

Other (OTH) AF: 0.0185 AC: 1090 AN: 59004

GnomAD4 genome AF: 0.0234 AC: 3567 AN: 152164 Hom.: 68 Cov.: 32 AF XY: 0.0226 AC XY: 1678 AN XY: 74386

African (AFR) AF: 0.0407 AC: 1690 AN: 41508

American (AMR) AF: 0.0194 AC: 296 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4830

European-Finnish (FIN) AF: 0.00359 AC: 38 AN: 10592

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0196 AC: 1335 AN: 67986

Other (OTH) AF: 0.0294 AC: 62 AN: 2110

Alfa AF: 0.0180 Hom.: 23

Bravo AF: 0.0253

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Progressive familial intrahepatic cholestasis type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Benign	0.70
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.024
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: rs11568363; hg19: chr2-169869774;