rs8187707

Variant names:

• chr10-99850776-C-T
• rs8187707
• NM_000392.5:c.4488C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000392.5(ABCC2):​c.4488C>T​(p.His1496His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,614,080 control chromosomes in the GnomAD database, including 2,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (192 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2323 hom.)
• Consequence: ABCC2 NM_000392.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.43
• Publications: 27 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 10-99850776-C-T is Benign according to our data. Variant chr10-99850776-C-T is described in ClinVar as Benign. ClinVar VariationId is 298479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000392.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	NM_000392.5	MANE Select	c.4488C>T	p.His1496His	synonymous	Exon 31 of 32	NP_000383.2	Q92887

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	ENST00000647814.1	MANE Select	c.4488C>T	p.His1496His	synonymous	Exon 31 of 32	ENSP00000497274.1	Q92887
	ABCC2	ENST00000648523.1		n.*329C>T		non_coding_transcript_exon	Exon 4 of 5	ENSP00000497778.1	A0A3B3ITG8
	ABCC2	ENST00000648523.1		n.*329C>T		3_prime_UTR	Exon 4 of 5	ENSP00000497778.1	A0A3B3ITG8

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7154 AN: 152186 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0557

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0679

GnomAD2 exomes AF: 0.0435 AC: 10925 AN: 251416 AF XY: 0.0443

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.0347

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0566

Gnomad OTH exome AF: 0.0606

GnomAD4 exome AF: 0.0523 AC: 76500 AN: 1461776 Hom.: 2323 Cov.: 32 AF XY: 0.0518 AC XY: 37664 AN XY: 727200

African (AFR) AF: 0.0360 AC: 1204 AN: 33480

American (AMR) AF: 0.0375 AC: 1677 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3430 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0185 AC: 1594 AN: 86254

European-Finnish (FIN) AF: 0.0232 AC: 1237 AN: 53410

Middle Eastern (MID) AF: 0.127 AC: 735 AN: 5768

European-Non Finnish (NFE) AF: 0.0567 AC: 63093 AN: 1111912

Other (OTH) AF: 0.0583 AC: 3518 AN: 60392

GnomAD4 genome AF: 0.0470 AC: 7165 AN: 152304 Hom.: 192 Cov.: 33 AF XY: 0.0452 AC XY: 3368 AN XY: 74470

African (AFR) AF: 0.0356 AC: 1480 AN: 41560

American (AMR) AF: 0.0556 AC: 851 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 422 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4832

European-Finnish (FIN) AF: 0.0222 AC: 236 AN: 10618

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.0566 AC: 3853 AN: 68016

Other (OTH) AF: 0.0676 AC: 143 AN: 2114

Alfa AF: 0.0568 Hom.: 607

Bravo AF: 0.0506

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0661

EpiControl AF: 0.0727

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ABCC2-related disorder (1)
-	-	1	Dubin-Johnson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.2
DANN	Benign	0.57
PhyloP100		3.4
Mutation Taster		=84/16	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: rs8187707; hg19: chr10-101610533; COSMIC: COSV64985819;