rs57509552

Variant names:

• chr2-168979878-C-A
• rs57509552
• NM_003742.4:c.1185G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-168979878-C-A
• chr2-168979878-C-G
• chr2-168979878-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003742.4(ABCB11):​c.1185G>T​(p.Glu395Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E395E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.163
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09815356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.1185G>T	p.Glu395Asp	missense_variant	Exon 11 of 28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.1185G>T	p.Glu395Asp	missense_variant	Exon 11 of 28		NM_003742.4	ENSP00000497931.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427420 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709624

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32554

American (AMR) AF: 0.00 AC: 0 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24976

East Asian (EAS) AF: 0.00 AC: 0 AN: 37588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090134

Other (OTH) AF: 0.00 AC: 0 AN: 58132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 56

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1185G>T (p.E395D) alteration is located in exon 11 (coding exon 10) of the ABCB11 gene. This alteration results from a G to T substitution at nucleotide position 1185, causing the glutamic acid (E) at amino acid position 395 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Progressive familial intrahepatic cholestasis type 2 Uncertain:1

Sep 07, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.66	.;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.63	N;.
REVEL	Benign	0.12
Sift	Benign	0.31	T;.
Sift4G	Benign	0.36	T;.
Polyphen		0.0020	B;B
Vest4		0.22
MutPred		0.40		Loss of methylation at K400 (P = 0.135);Loss of methylation at K400 (P = 0.135);
MVP		0.72
MPC		0.13
ClinPred		0.13	T
GERP RS		-1.7
Varity_R		0.055
gMVP		0.82
Mutation Taster		=70/30	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: rs57509552; hg19: chr2-169836388;