2-168923386-T-C

Position:

• chr2-168923386-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003742.4(ABCB11):​c.*236A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 570,900 control chromosomes in the GnomAD database, including 112,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30228 hom., cov: 30)
  • Exomes 𝑓: 0.62 (82358 hom.)
• Consequence: ABCB11 NM_003742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.225

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-168923386-T-C is Benign according to our data. Variant chr2-168923386-T-C is described in ClinVar as [Benign]. Clinvar id is 332018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB11	NM_003742.4	c.*236A>G		3_prime_UTR_variant	28/28	ENST00000650372.1
ABCB11	XM_011512078.3	c.*190A>G		3_prime_UTR_variant	29/29
ABCB11	XM_017005165.2	c.3867+1271A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.*236A>G		3_prime_UTR_variant	28/28		NM_003742.4	P1
ABCB11	ENST00000649448.1	c.*236A>G		3_prime_UTR_variant	15/15
ABCB11	ENST00000648875.1	c.226+1271A>G		intron_variant
ABCB11	ENST00000439188.1	c.*2600A>G		3_prime_UTR_variant, NMD_transcript_variant	15/15	2

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94766 AN: 151856 Hom.: 30197 Cov.: 30

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.927

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.616 AC: 257905 AN: 418926 Hom.: 82358 Cov.: 4 AF XY: 0.623 AC XY: 137126 AN XY: 220164

Gnomad4 AFR exome AF: 0.683

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.656

Gnomad4 EAS exome AF: 0.940

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.598

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.616

GnomAD4 genome AF: 0.624 AC: 94858 AN: 151974 Hom.: 30228 Cov.: 30 AF XY: 0.633 AC XY: 47025 AN XY: 74282

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.629

Gnomad4 ASJ AF: 0.651

Gnomad4 EAS AF: 0.927

Gnomad4 SAS AF: 0.771

Gnomad4 FIN AF: 0.611

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.616

Alfa AF: 0.568 Hom.: 41434

Bravo AF: 0.624

Asia WGS AF: 0.803 AC: 2792 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Progressive familial intrahepatic cholestasis type 2 Benign:1

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	-0.90
CADD	Benign	2.7
DANN	Benign	0.61

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: rs473351; hg19: chr2-169779896;