rs4148398

Variant names:

• chr10-99832865-A-G
• rs4148398
• NM_000392.5:c.3258+734A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000392.5(ABCC2):​c.3258+734A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 152,114 control chromosomes in the GnomAD database, including 37,618 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (37618 hom., cov: 33)
• Consequence: ABCC2 NM_000392.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.3258+734A>G		intron_variant	Intron 23 of 31	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.2562+734A>G		intron_variant	Intron 18 of 26		XP_006717693.1
ABCC2	XM_047424598.1	c.3258+734A>G		intron_variant	Intron 23 of 25		XP_047280554.1
ABCC2	XR_945604.4	n.3463+734A>G		intron_variant	Intron 23 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.3258+734A>G		intron_variant	Intron 23 of 31		NM_000392.5	ENSP00000497274.1

Frequencies

GnomAD3 genomes AF: 0.697 AC: 106014 AN: 151996 Hom.: 37574 Cov.: 33

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.667

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.698 AC: 106123 AN: 152114 Hom.: 37618 Cov.: 33 AF XY: 0.698 AC XY: 51901 AN XY: 74356

African (AFR) AF: 0.815 AC: 33819 AN: 41490

American (AMR) AF: 0.663 AC: 10122 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2257 AN: 3472

East Asian (EAS) AF: 0.768 AC: 3985 AN: 5186

South Asian (SAS) AF: 0.717 AC: 3455 AN: 4822

European-Finnish (FIN) AF: 0.657 AC: 6938 AN: 10558

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43488 AN: 67988

Other (OTH) AF: 0.666 AC: 1410 AN: 2116

Alfa AF: 0.652 Hom.: 53916

Bravo AF: 0.704

Asia WGS AF: 0.747 AC: 2597 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.47
DANN	Benign	0.31
PhyloP100		-1.0
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: rs4148398; hg19: chr10-101592622;