rs11568377

Positions:

• chr2-168996710-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003742.4(ABCB11):​c.402C>T​(p.Ile134Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,560,136 control chromosomes in the GnomAD database, including 1,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (628 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (505 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.894

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-168996710-G-A is Benign according to our data. Variant chr2-168996710-G-A is described in ClinVar as [Benign]. Clinvar id is 259155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.894 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.402C>T	p.Ile134Ile	synonymous_variant	6/28	ENST00000650372.1	NP_003733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1	c.402C>T	p.Ile134Ile	synonymous_variant	6/28		NM_003742.4	ENSP00000497931.1

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7529 AN: 151550 Hom.: 622 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000736

Gnomad OTH AF: 0.0322

GnomAD3 exomes AF: 0.0132 AC: 2581 AN: 196230 Hom.: 159 AF XY: 0.0107 AC XY: 1123 AN XY: 105068

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.00804

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000497

Gnomad SAS exome AF: 0.0166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00575 AC: 8097 AN: 1408486 Hom.: 505 Cov.: 29 AF XY: 0.00540 AC XY: 3764 AN XY: 697598

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000319

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000319

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0498 AC: 7559 AN: 151650 Hom.: 628 Cov.: 31 AF XY: 0.0476 AC XY: 3527 AN XY: 74124

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000736

Gnomad4 OTH AF: 0.0319

Alfa AF: 0.0123 Hom.: 261

Bravo AF: 0.0570

Asia WGS AF: 0.0210 AC: 74 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Progressive familial intrahepatic cholestasis type 2 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.8
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs11568377; hg19: chr2-169853220;