rs11568359

Variant names:

• chr2-168930818-T-C
• rs11568359
• NM_003742.4:c.3258A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003742.4(ABCB11):​c.3258A>G​(p.Thr1086Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,611,290 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (135 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.07
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-168930818-T-C is Benign according to our data. Variant chr2-168930818-T-C is described in ClinVar as Benign. ClinVar VariationId is 259153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0839 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.3258A>G	p.Thr1086Thr	synonymous	Exon 25 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.3258A>G	p.Thr1086Thr	synonymous	Exon 25 of 28	ENSP00000497931.1
	ABCB11	ENST00000858973.1		c.3300A>G	p.Thr1100Thr	synonymous	Exon 25 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.3153A>G	p.Thr1051Thr	synonymous	Exon 24 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3739 AN: 152152 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00597 AC: 1453 AN: 243470 AF XY: 0.00445

Gnomad AFR exome AF: 0.0870

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000254

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00245 AC: 3569 AN: 1459020 Hom.: 135 Cov.: 31 AF XY: 0.00213 AC XY: 1543 AN XY: 725502

African (AFR) AF: 0.0896 AC: 2996 AN: 33440

American (AMR) AF: 0.00358 AC: 159 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.000109 AC: 121 AN: 1110700

Other (OTH) AF: 0.00441 AC: 266 AN: 60286

GnomAD4 genome AF: 0.0246 AC: 3741 AN: 152270 Hom.: 133 Cov.: 32 AF XY: 0.0235 AC XY: 1749 AN XY: 74476

African (AFR) AF: 0.0863 AC: 3582 AN: 41520

American (AMR) AF: 0.00725 AC: 111 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00878 Hom.: 41

Bravo AF: 0.0272

Asia WGS AF: 0.00318 AC: 11 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)
-	-	2	Progressive familial intrahepatic cholestasis type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.0
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=91/9	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: rs11568359; hg19: chr2-169787328;