2-168964250-A-G

Position:

• chr2-168964250-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003742.4(ABCB11):​c.2134T>C​(p.Leu712Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,570,236 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (34 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.377

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-168964250-A-G is Benign according to our data. Variant chr2-168964250-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168964250-A-G is described in Lovd as [Benign]. Variant chr2-168964250-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.377 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00513 (7274/1418400) while in subpopulation MID AF= 0.0121 (69/5690). AF 95% confidence interval is 0.00983. There are 34 homozygotes in gnomad4_exome. There are 3466 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4	c.2134T>C	p.Leu712Leu	synonymous_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.2134T>C	p.Leu712Leu	synonymous_variant	18/28		NM_003742.4	ENSP00000497931.1
ABCB11	ENST00000649448.1	c.451T>C	p.Leu151Leu	synonymous_variant	4/15			ENSP00000497165.1
ABCB11	ENST00000439188.1	n.*604T>C		non_coding_transcript_exon_variant	5/15	2		ENSP00000416058.1
ABCB11	ENST00000439188.1	n.*604T>C		3_prime_UTR_variant	5/15	2		ENSP00000416058.1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 612 AN: 151718 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00823

Gnomad ASJ AF: 0.00780

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00583

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00417 AC: 792 AN: 189988 Hom.: 7 AF XY: 0.00416 AC XY: 420 AN XY: 100974

Gnomad AFR exome AF: 0.000872

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00138

Gnomad FIN exome AF: 0.00233

Gnomad NFE exome AF: 0.00589

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.00513 AC: 7274 AN: 1418400 Hom.: 34 Cov.: 30 AF XY: 0.00494 AC XY: 3466 AN XY: 701412

Gnomad4 AFR exome AF: 0.000920

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.00780

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.00299

Gnomad4 NFE exome AF: 0.00574

Gnomad4 OTH exome AF: 0.00539

GnomAD4 genome AF: 0.00403 AC: 612 AN: 151836 Hom.: 5 Cov.: 32 AF XY: 0.00431 AC XY: 320 AN XY: 74196

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.00822

Gnomad4 ASJ AF: 0.00780

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00583

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00565 Hom.: 2

Bravo AF: 0.00414

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2018	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	Eurofins Ntd Llc (ga)	Aug 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABCB11: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Progressive familial intrahepatic cholestasis type 2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -
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	-0.75
CADD	Benign	0.80
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs191649793; hg19: chr2-169820760;