rs11568378

Variant names:

• chr2-168996619-C-T
• rs11568378
• NM_003742.4:c.477+16G>A

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.477+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,408,792 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (626 hom., cov: 31)
  • Exomes 𝑓: 0.0056 (435 hom.)
• Consequence: ABCB11 NM_003742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.31
• 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=-0.92).
• BP6: Variant 2-168996619-C-T is Benign according to our data. Variant chr2-168996619-C-T is described in ClinVar as Benign. ClinVar VariationId is 259156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	NM_003742.4	MANE Select	c.477+16G>A		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.477+16G>A		intron	N/A	ENSP00000497931.1

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7544 AN: 151704 Hom.: 620 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000839

Gnomad OTH AF: 0.0331

GnomAD2 exomes AF: 0.0117 AC: 1708 AN: 145666 AF XY: 0.00960

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.00764

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000729

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000719

Gnomad OTH exome AF: 0.00422

GnomAD4 exome AF: 0.00561 AC: 7053 AN: 1256970 Hom.: 435 Cov.: 19 AF XY: 0.00528 AC XY: 3278 AN XY: 621412

African (AFR) AF: 0.164 AC: 4536 AN: 27618

American (AMR) AF: 0.0108 AC: 331 AN: 30750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22150

East Asian (EAS) AF: 0.000312 AC: 10 AN: 32040

South Asian (SAS) AF: 0.0158 AC: 958 AN: 60504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46598

Middle Eastern (MID) AF: 0.00813 AC: 42 AN: 5168

European-Non Finnish (NFE) AF: 0.000475 AC: 466 AN: 980836

Other (OTH) AF: 0.0138 AC: 710 AN: 51306

GnomAD4 genome AF: 0.0499 AC: 7577 AN: 151822 Hom.: 626 Cov.: 31 AF XY: 0.0477 AC XY: 3541 AN XY: 74234

African (AFR) AF: 0.170 AC: 7039 AN: 41390

American (AMR) AF: 0.0205 AC: 311 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000839 AC: 57 AN: 67906

Other (OTH) AF: 0.0328 AC: 69 AN: 2104

Alfa AF: 0.0173 Hom.: 273

Bravo AF: 0.0571

Asia WGS AF: 0.0210 AC: 74 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.010
DANN	Benign	0.60
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11568378; hg19: chr2-169853129; COSMIC: COSV104379524;