rs4148396

Variant names:

• chr10-99832187-T-C
• rs4148396
• NM_000392.5:c.3258+56T>C

Variant summary

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

The NM_000392.5(ABCC2):​c.3258+56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,606,194 control chromosomes in the GnomAD database, including 310,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32450 hom., cov: 31)
  • Exomes 𝑓: 0.62 (278344 hom.)
• Consequence: ABCC2 NM_000392.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.310
• Publications: 31 publications found

Genes affected

ABCC2 (HGNC:53): (ATP binding cassette subfamily C member 2) The 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 MRP subfamily which is involved in multi-drug resistance. This protein is expressed in the canalicular (apical) part of the hepatocyte and functions in biliary transport. Substrates include anticancer drugs such as vinblastine; therefore, this protein appears to contribute to drug resistance in mammalian cells. Several different mutations in this gene have been observed in patients with Dubin-Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia. [provided by RefSeq, Jul 2008]

ABCC2 Gene-Disease associations (from GenCC):

• Dubin-Johnson syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-99832187-T-C is Benign according to our data. Variant chr10-99832187-T-C is described in ClinVar as Benign. ClinVar VariationId is 1188977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.3258+56T>C		intron_variant	Intron 23 of 31	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.2562+56T>C		intron_variant	Intron 18 of 26		XP_006717693.1
ABCC2	XM_047424598.1	c.3258+56T>C		intron_variant	Intron 23 of 25		XP_047280554.1
ABCC2	XR_945604.4	n.3463+56T>C		intron_variant	Intron 23 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.3258+56T>C		intron_variant	Intron 23 of 31		NM_000392.5	ENSP00000497274.1

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98805 AN: 151874 Hom.: 32438 Cov.: 31

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.641

GnomAD4 exome AF: 0.617 AC: 897707 AN: 1454202 Hom.: 278344 AF XY: 0.617 AC XY: 446840 AN XY: 723754

African (AFR) AF: 0.716 AC: 23880 AN: 33336

American (AMR) AF: 0.642 AC: 28562 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 16669 AN: 26066

East Asian (EAS) AF: 0.775 AC: 30737 AN: 39644

South Asian (SAS) AF: 0.636 AC: 54720 AN: 85994

European-Finnish (FIN) AF: 0.642 AC: 34230 AN: 53322

Middle Eastern (MID) AF: 0.676 AC: 3639 AN: 5386

European-Non Finnish (NFE) AF: 0.604 AC: 667633 AN: 1105854

Other (OTH) AF: 0.626 AC: 37637 AN: 60082

GnomAD4 genome AF: 0.650 AC: 98863 AN: 151992 Hom.: 32450 Cov.: 31 AF XY: 0.652 AC XY: 48428 AN XY: 74296

African (AFR) AF: 0.712 AC: 29484 AN: 41418

American (AMR) AF: 0.635 AC: 9690 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2196 AN: 3466

East Asian (EAS) AF: 0.779 AC: 4035 AN: 5180

South Asian (SAS) AF: 0.637 AC: 3063 AN: 4806

European-Finnish (FIN) AF: 0.655 AC: 6912 AN: 10560

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41515 AN: 67974

Other (OTH) AF: 0.637 AC: 1348 AN: 2116

Alfa AF: 0.625 Hom.: 97084

Bravo AF: 0.655

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dubin-Johnson syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.6
DANN	Benign	0.54
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4148396; hg19: chr10-101591944;