NM_000392.5:c.4488C>T

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: Orphanet, Labcorp Genetics (formerly Invitae)

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.4488C>T	p.His1496His	synonymous_variant	Exon 31 of 32	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.3792C>T	p.His1264His	synonymous_variant	Exon 26 of 27		XP_006717693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.4488C>T	p.His1496His	synonymous_variant	Exon 31 of 32		NM_000392.5	ENSP00000497274.1
ABCC2	ENST00000648523.1	n.*329C>T		non_coding_transcript_exon_variant	Exon 4 of 5			ENSP00000497778.1
ABCC2	ENST00000648523.1	n.*329C>T		3_prime_UTR_variant	Exon 4 of 5			ENSP00000497778.1
ABCC2	ENST00000649459.1	n.*63C>T		downstream_gene_variant

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCC2-related disorder Benign:1

Oct 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dubin-Johnson syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.36
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;