rs2287616

chr2-168990902-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003742.4(ABCB11):c.807T>C(p.Tyr269=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,022 control chromosomes in the GnomAD database, including 2,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (254 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1827 hom.)
• Consequence: ABCB11 NM_003742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.104

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=-0.84).
• BP6: Variant 2-168990902-A-G is Benign according to our data. Variant chr2-168990902-A-G is described in ClinVar as [Benign]. Clinvar id is 259157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.104 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4	c.807T>C	p.Tyr269=	synonymous_variant	9/28	ENST00000650372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.807T>C	p.Tyr269=	synonymous_variant	9/28		NM_003742.4	P1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2307 AN: 152164 Hom.: 255 Cov.: 32

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0327 AC: 8111 AN: 248324 Hom.: 877 AF XY: 0.0282 AC XY: 3797 AN XY: 134674

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.00967

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000881

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0117 AC: 17110 AN: 1460740 Hom.: 1827 Cov.: 31 AF XY: 0.0112 AC XY: 8174 AN XY: 726650

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.0529

Gnomad4 ASJ exome AF: 0.00935

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000687

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0151 AC: 2305 AN: 152282 Hom.: 254 Cov.: 32 AF XY: 0.0163 AC XY: 1214 AN XY: 74450

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00505 Hom.: 68

Bravo AF: 0.0199

Asia WGS AF: 0.140 AC: 485 AN: 3476

EpiCase AF: 0.00115

EpiControl AF: 0.000653

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 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	-	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.6
Dann	Benign	0.27

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: rs2287616; hg19: chr2-169847412; COSMIC: COSV55591248;