chr2-168957837-A-G

Variant names:

• chr2-168957837-A-G
• rs853773
• NM_003742.4:c.2343+127T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003742.4(ABCB11):​c.2343+127T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 986,868 control chromosomes in the GnomAD database, including 148,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24209 hom., cov: 31)
  • Exomes 𝑓: 0.55 (124739 hom.)
• Consequence: ABCB11 NM_003742.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.131
• Publications: 8 publications found

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]

ABCB11 Gene-Disease associations (from GenCC):

• progressive familial intrahepatic cholestasis type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• benign recurrent intrahepatic cholestasis type 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-168957837-A-G is Benign according to our data. Variant chr2-168957837-A-G is described in ClinVar as Benign. ClinVar VariationId is 1294312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	NM_003742.4	MANE Select	c.2343+127T>C		intron	N/A	NP_003733.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB11	ENST00000650372.1	MANE Select	c.2343+127T>C		intron	N/A	ENSP00000497931.1
	ABCB11	ENST00000649448.1		c.660+127T>C		intron	N/A	ENSP00000497165.1
	ABCB11	ENST00000439188.1	TSL:2	n.*813+127T>C		intron	N/A	ENSP00000416058.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85261 AN: 151254 Hom.: 24197 Cov.: 31

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.564

GnomAD4 exome AF: 0.545 AC: 455517 AN: 835496 Hom.: 124739 AF XY: 0.545 AC XY: 220899 AN XY: 405406

African (AFR) AF: 0.626 AC: 12409 AN: 19832

American (AMR) AF: 0.585 AC: 8101 AN: 13850

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 8587 AN: 13716

East Asian (EAS) AF: 0.619 AC: 18560 AN: 29970

South Asian (SAS) AF: 0.605 AC: 13683 AN: 22616

European-Finnish (FIN) AF: 0.519 AC: 13498 AN: 26018

Middle Eastern (MID) AF: 0.571 AC: 1675 AN: 2936

European-Non Finnish (NFE) AF: 0.535 AC: 358459 AN: 670326

Other (OTH) AF: 0.567 AC: 20545 AN: 36232

GnomAD4 genome AF: 0.564 AC: 85325 AN: 151372 Hom.: 24209 Cov.: 31 AF XY: 0.565 AC XY: 41808 AN XY: 73932

African (AFR) AF: 0.608 AC: 25147 AN: 41334

American (AMR) AF: 0.564 AC: 8557 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2146 AN: 3456

East Asian (EAS) AF: 0.646 AC: 3284 AN: 5084

South Asian (SAS) AF: 0.593 AC: 2853 AN: 4808

European-Finnish (FIN) AF: 0.533 AC: 5624 AN: 10550

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35718 AN: 67646

Other (OTH) AF: 0.561 AC: 1180 AN: 2104

Alfa AF: 0.522 Hom.: 9990

Bravo AF: 0.569

Asia WGS AF: 0.638 AC: 2217 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.8
DANN	Benign	0.59
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs853773; hg19: chr2-169814347;