rs201800225

Positions:

• chr2-168964259-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003742.4(ABCB11):​c.2125G>A​(p.Glu709Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,570,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014417946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.2125G>A	p.Glu709Lys	missense_variant	18/28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.2125G>A	p.Glu709Lys	missense_variant	18/28		NM_003742.4	ENSP00000497931.1
ABCB11	ENST00000649448.1	c.442G>A	p.Glu148Lys	missense_variant	4/15			ENSP00000497165.1
ABCB11	ENST00000439188.1	n.*595G>A		non_coding_transcript_exon_variant	5/15	2		ENSP00000416058.1
ABCB11	ENST00000439188.1	n.*595G>A		3_prime_UTR_variant	5/15	2		ENSP00000416058.1

Frequencies

GnomAD3 genomes AF: 0.0000659 AC: 10 AN: 151684 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000210 AC: 40 AN: 190272 Hom.: 0 AF XY: 0.000217 AC XY: 22 AN XY: 101154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000641

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000448

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 187 AN: 1419170 Hom.: 0 Cov.: 30 AF XY: 0.000137 AC XY: 96 AN XY: 701934

Gnomad4 AFR exome AF: 0.0000613

Gnomad4 AMR exome AF: 0.000567

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.000384

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.000170

GnomAD4 genome AF: 0.0000659 AC: 10 AN: 151684 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74034

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000109 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Reported in one patient with intrahepatic cholestasis of pregnancy in published literature (Aydin et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19101985, 32808743, 32917322) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2022	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

ABCB11-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2024

The ABCB11 c.2125G>A variant is predicted to result in the amino acid substitution p.Glu709Lys. This variant was previously reported in the heterozygous state in an individual with intrahepatic cholestasis of pregnancy; however, the authors suggested that this variant may be benign (Adanas Aydin et al. 2020. PubMed ID: 32917322). In addition, this variant was reported in a study of the ABCB11 gene, but its clinical significance was unknown (Byrne et al., 2009. PubMed ID: 19101985). Finally, it's been detected in an adult female with chronic liver disease and pregnancy-associated liver dysfunction (Nayagam et al. 2022. PubMed ID: 35894240). This variant is reported in 0.066% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Benign recurrent intrahepatic cholestasis type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 29, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.88	N;.;.
REVEL	Benign	0.23
Sift	Benign	0.31	T;.;.
Sift4G	Benign	0.49	T;.;.
Polyphen		0.15	B;B;.
Vest4		0.32
MVP		0.84
MPC		0.17
ClinPred		0.041	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201800225; hg19: chr2-169820769; COSMIC: COSV105848218;