rs11568367

Positions:

• chr2-168970082-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_003742.4(ABCB11):​c.1772A>G​(p.Asn591Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00658 in 1,612,642 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (595 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.27

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_003742.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026473403).
• BP6: Variant 2-168970082-T-C is Benign according to our data. Variant chr2-168970082-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 194505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168970082-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4	c.1772A>G	p.Asn591Ser	missense_variant	15/28	ENST00000650372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.1772A>G	p.Asn591Ser	missense_variant	15/28		NM_003742.4	P1
ABCB11	ENST00000649448.1	c.89A>G	p.Asn30Ser	missense_variant	1/15
ABCB11	ENST00000478354.1	n.510A>G		non_coding_transcript_exon_variant	1/2	4
ABCB11	ENST00000439188.1	c.*242A>G		3_prime_UTR_variant, NMD_transcript_variant	2/15	2

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 634 AN: 151928 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.0142 AC: 3525 AN: 248634 Hom.: 225 AF XY: 0.0194 AC XY: 2617 AN XY: 134866

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00223

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00530

GnomAD4 exome AF: 0.00683 AC: 9977 AN: 1460596 Hom.: 595 Cov.: 33 AF XY: 0.0100 AC XY: 7291 AN XY: 726614

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000958

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00685

GnomAD4 genome AF: 0.00415 AC: 631 AN: 152046 Hom.: 45 Cov.: 32 AF XY: 0.00612 AC XY: 455 AN XY: 74330

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000510 Hom.: 5

Bravo AF: 0.00114

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00102 AC: 4

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.0158 AC: 1909

Asia WGS AF: 0.0320 AC: 110 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -

Progressive familial intrahepatic cholestasis type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D;D
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-0.67	N;N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.84	N;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.20	T;.;.
Polyphen		0.98	D;D;.
Vest4		0.69
MPC		0.51
ClinPred		0.017	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11568367; hg19: chr2-169826592;