2-168932506-T-C

Variant names:

• chr2-168932506-T-C
• rs497692
• NM_003742.4:c.3084A>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.3084A>G​(p.Ala1028Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 1,612,724 control chromosomes in the GnomAD database, including 234,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1028A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.47 (18356 hom., cov: 32)
  • Exomes 𝑓: 0.54 (216366 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.53
• Publications: 58 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=-0.87).
• BP6: Variant 2-168932506-T-C is Benign according to our data. Variant chr2-168932506-T-C is described in ClinVar as Benign. ClinVar VariationId is 259152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.636 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.3084A>G	p.Ala1028Ala	synonymous	Exon 24 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.3084A>G	p.Ala1028Ala	synonymous	Exon 24 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.3126A>G	p.Ala1042Ala	synonymous	Exon 24 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.2979A>G	p.Ala993Ala	synonymous	Exon 23 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71727 AN: 151934 Hom.: 18361 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.498

GnomAD2 exomes AF: 0.555 AC: 137322 AN: 247640 AF XY: 0.561

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.602

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.619

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.536

Gnomad OTH exome AF: 0.549

GnomAD4 exome AF: 0.541 AC: 790142 AN: 1460672 Hom.: 216366 Cov.: 47 AF XY: 0.545 AC XY: 396148 AN XY: 726506

African (AFR) AF: 0.261 AC: 8742 AN: 33472

American (AMR) AF: 0.588 AC: 26203 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16266 AN: 26120

East Asian (EAS) AF: 0.590 AC: 23424 AN: 39684

South Asian (SAS) AF: 0.658 AC: 56646 AN: 86056

European-Finnish (FIN) AF: 0.551 AC: 29397 AN: 53364

Middle Eastern (MID) AF: 0.567 AC: 3272 AN: 5766

European-Non Finnish (NFE) AF: 0.534 AC: 593441 AN: 1111290

Other (OTH) AF: 0.543 AC: 32751 AN: 60340

GnomAD4 genome AF: 0.472 AC: 71733 AN: 152052 Hom.: 18356 Cov.: 32 AF XY: 0.480 AC XY: 35634 AN XY: 74308

African (AFR) AF: 0.269 AC: 11134 AN: 41458

American (AMR) AF: 0.512 AC: 7838 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2127 AN: 3470

East Asian (EAS) AF: 0.626 AC: 3227 AN: 5156

South Asian (SAS) AF: 0.655 AC: 3153 AN: 4814

European-Finnish (FIN) AF: 0.559 AC: 5904 AN: 10554

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36458 AN: 67986

Other (OTH) AF: 0.492 AC: 1039 AN: 2112

Alfa AF: 0.512 Hom.: 69025

Bravo AF: 0.457

Asia WGS AF: 0.603 AC: 2095 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Progressive familial intrahepatic cholestasis type 2 (3)
-	-	2	not provided (2)
-	-	1	Benign recurrent intrahepatic cholestasis type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.041
DANN	Benign	0.41
PhyloP100		-3.5
Mutation Taster		=98/2	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: rs497692; hg19: chr2-169789016; COSMIC: COSV55585329;