2-168970080-C-T

Variant names:

• chr2-168970080-C-T
• rs11568370
• NM_003742.4:c.1774G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_003742.4(ABCB11):​c.1774G>A​(p.Glu592Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E592Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.11
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_003742.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

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.1774G>A	p.Glu592Lys	missense	Exon 15 of 28	NP_003733.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.1774G>A	p.Glu592Lys	missense	Exon 15 of 28	ENSP00000497931.1
	ABCB11	ENST00000649448.1		c.91G>A	p.Glu31Lys	missense	Exon 1 of 15	ENSP00000497165.1
	ABCB11	ENST00000439188.1	TSL:2	n.*244G>A		non_coding_transcript_exon	Exon 2 of 15	ENSP00000416058.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460724 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726674

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111210

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.5	L
PhyloP100		6.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.76
Sift	Benign	0.032	D
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.59		Gain of ubiquitination at E592 (P = 0.0155)
MVP		0.90
MPC		0.67
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		-0.060	Neutral
Varity_R		0.60
gMVP		0.73
Mutation Taster		=4/96	disease causing

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: rs11568370; hg19: chr2-169826590;