rs496550

Variant names:

• chr2-168923202-T-C
• rs496550
• NM_003742.4:c.*420A>G

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.*420A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 175,774 control chromosomes in the GnomAD database, including 22,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18879 hom., cov: 32)
  • Exomes 𝑓: 0.50 (3236 hom.)
• Consequence: ABCB11 NM_003742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.236
• Publications: 17 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: Orphanet, G2P, 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=-0.91).
• BP6: Variant 2-168923202-T-C is Benign according to our data. Variant chr2-168923202-T-C is described in ClinVar as Benign. ClinVar VariationId is 332013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.*420A>G		3_prime_UTR	Exon 28 of 28	NP_003733.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.*420A>G		3_prime_UTR	Exon 28 of 28	ENSP00000497931.1	O95342
	ABCB11	ENST00000858973.1		c.*420A>G		3_prime_UTR	Exon 28 of 28	ENSP00000529032.1
	ABCB11	ENST00000858972.1		c.*420A>G		3_prime_UTR	Exon 27 of 27	ENSP00000529031.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73358 AN: 151866 Hom.: 18880 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.512

GnomAD4 exome AF: 0.505 AC: 12005 AN: 23790 Hom.: 3236 Cov.: 0 AF XY: 0.511 AC XY: 6275 AN XY: 12274

African (AFR) AF: 0.249 AC: 216 AN: 868

American (AMR) AF: 0.544 AC: 1344 AN: 2472

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 377 AN: 598

East Asian (EAS) AF: 0.541 AC: 796 AN: 1472

South Asian (SAS) AF: 0.612 AC: 949 AN: 1550

European-Finnish (FIN) AF: 0.470 AC: 348 AN: 740

Middle Eastern (MID) AF: 0.485 AC: 32 AN: 66

European-Non Finnish (NFE) AF: 0.496 AC: 7309 AN: 14748

Other (OTH) AF: 0.497 AC: 634 AN: 1276

GnomAD4 genome AF: 0.483 AC: 73380 AN: 151984 Hom.: 18879 Cov.: 32 AF XY: 0.490 AC XY: 36396 AN XY: 74282

African (AFR) AF: 0.302 AC: 12549 AN: 41488

American (AMR) AF: 0.517 AC: 7905 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2171 AN: 3468

East Asian (EAS) AF: 0.625 AC: 3227 AN: 5162

South Asian (SAS) AF: 0.655 AC: 3147 AN: 4804

European-Finnish (FIN) AF: 0.560 AC: 5911 AN: 10550

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.538 AC: 36546 AN: 67914

Other (OTH) AF: 0.507 AC: 1068 AN: 2108

Alfa AF: 0.518 Hom.: 78027

Bravo AF: 0.470

Asia WGS AF: 0.605 AC: 2102 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.30
PhyloP100		-0.24
Mutation Taster		=100/0	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: rs496550; hg19: chr2-169779712; COSMIC: COSV55595495; COSMIC: COSV55595495;