chr2-168973818-A-G

Variant names:

• chr2-168973818-A-G
• rs2287622
• NM_003742.4:c.1331T>C

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.1331T>C​(p.Val444Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,610,750 control chromosomes in the GnomAD database, including 282,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25038 hom., cov: 30)
  • Exomes 𝑓: 0.59 (257725 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.39
• Publications: 164 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 (MetaRNN=2.0099598E-5).
• BP6: Variant 2-168973818-A-G is Benign according to our data. Variant chr2-168973818-A-G is described in ClinVar as Benign. ClinVar VariationId is 194214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 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.1331T>C	p.Val444Ala	missense	Exon 13 of 28	NP_003733.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.1331T>C	p.Val444Ala	missense	Exon 13 of 28	ENSP00000497931.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86689 AN: 151500 Hom.: 25023 Cov.: 30

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.569 AC: 141494 AN: 248542 AF XY: 0.574

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.558

Gnomad EAS exome AF: 0.728

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.593 AC: 864780 AN: 1459132 Hom.: 257725 Cov.: 40 AF XY: 0.592 AC XY: 429695 AN XY: 725906

African (AFR) AF: 0.578 AC: 19267 AN: 33362

American (AMR) AF: 0.424 AC: 18935 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14663 AN: 26024

East Asian (EAS) AF: 0.728 AC: 28857 AN: 39646

South Asian (SAS) AF: 0.569 AC: 49040 AN: 86182

European-Finnish (FIN) AF: 0.512 AC: 27330 AN: 53360

Middle Eastern (MID) AF: 0.584 AC: 3356 AN: 5746

European-Non Finnish (NFE) AF: 0.602 AC: 667981 AN: 1109968

Other (OTH) AF: 0.587 AC: 35351 AN: 60210

GnomAD4 genome AF: 0.572 AC: 86740 AN: 151618 Hom.: 25038 Cov.: 30 AF XY: 0.566 AC XY: 41919 AN XY: 74026

African (AFR) AF: 0.567 AC: 23421 AN: 41320

American (AMR) AF: 0.463 AC: 7017 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1997 AN: 3472

East Asian (EAS) AF: 0.716 AC: 3672 AN: 5126

South Asian (SAS) AF: 0.568 AC: 2733 AN: 4812

European-Finnish (FIN) AF: 0.511 AC: 5386 AN: 10532

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40528 AN: 67890

Other (OTH) AF: 0.583 AC: 1222 AN: 2096

Alfa AF: 0.587 Hom.: 79180

Bravo AF: 0.571

TwinsUK AF: 0.602 AC: 2231

ALSPAC AF: 0.611 AC: 2354

ESP6500AA AF: 0.586 AC: 2194

ESP6500EA AF: 0.600 AC: 4941

ExAC AF: 0.579 AC: 69942

Asia WGS AF: 0.659 AC: 2292 AN: 3476

EpiCase AF: 0.608

EpiControl AF: 0.611

ClinVar

ClinVar submissions as Germline

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)
-	-	1	Benign recurrent intrahepatic cholestasis type 2 (1)
-	-	1	Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.000020	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.26
Sift	Benign	0.25	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.055
MPC		0.17
ClinPred		0.013	T
GERP RS		4.6
Varity_R		0.10
gMVP		0.68
Mutation Taster		=53/47	polymorphism

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: rs2287622; hg19: chr2-169830328; COSMIC: COSV55585312; COSMIC: COSV55585312;