2-168923254-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003742.4(ABCB11):c.*368G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 284,080 control chromosomes in the GnomAD database, including 39,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (18766 hom., cov: 31)
  • Exomes 𝑓: 0.55 (20243 hom.)
• Consequence: ABCB11 NM_003742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.56

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-168923254-C-T is Benign according to our data. Variant chr2-168923254-C-T is described in ClinVar as [Benign]. Clinvar id is 332014.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4	c.*368G>A		3_prime_UTR_variant	28/28	ENST00000650372.1
ABCB11	XM_011512078.3	c.*322G>A		3_prime_UTR_variant	29/29
ABCB11	XM_017005165.2	c.3867+1403G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.*368G>A		3_prime_UTR_variant	28/28		NM_003742.4	P1
ABCB11	ENST00000649448.1	c.*368G>A		3_prime_UTR_variant	15/15
ABCB11	ENST00000648875.1	c.226+1403G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73158 AN: 151852 Hom.: 18767 Cov.: 31

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.509

GnomAD4 exome AF: 0.545 AC: 72050 AN: 132108 Hom.: 20243 Cov.: 0 AF XY: 0.554 AC XY: 37878 AN XY: 68402

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.564

Gnomad4 ASJ exome AF: 0.615

Gnomad4 EAS exome AF: 0.597

Gnomad4 SAS exome AF: 0.660

Gnomad4 FIN exome AF: 0.544

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.542

GnomAD4 genome AF: 0.482 AC: 73181 AN: 151972 Hom.: 18766 Cov.: 31 AF XY: 0.489 AC XY: 36310 AN XY: 74284

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.655

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.503

Alfa AF: 0.526 Hom.: 38235

Bravo AF: 0.468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.89
Cadd	Benign	0.39
Dann	Benign	0.74

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: rs495714; hg19: chr2-169779764; COSMIC: COSV105056777; COSMIC: COSV105056777;