2-168923182-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003742.4(ABCB11):c.*440G>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 0.00113 in 166,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: ABCB11 NM_003742.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.529

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-168923182-C-T is Benign according to our data. Variant chr2-168923182-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 332012.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4	c.*440G>A		3_prime_UTR_variant	28/28	ENST00000650372.1
ABCB11	XM_011512078.3	c.*394G>A		3_prime_UTR_variant	29/29
ABCB11	XM_017005165.2	c.3867+1475G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.*440G>A		3_prime_UTR_variant	28/28		NM_003742.4	P1
ABCB11	ENST00000649448.1	c.*440G>A		3_prime_UTR_variant	15/15
ABCB11	ENST00000648875.1	c.226+1475G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.000720 AC: 10 AN: 13886 Hom.: 0 Cov.: 0 AF XY: 0.000822 AC XY: 6 AN XY: 7302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000539

Gnomad4 ASJ exome AF: 0.00313

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00207

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000703

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74414

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000877 Hom.: 0

Bravo AF: 0.00133

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 2 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.0
Dann	Benign	0.60

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: rs79130028; hg19: chr2-169779692;