rs2273697

Variant names:

• chr10-99804058-G-A
• rs2273697
• NM_000392.5:c.1249G>A

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.1249G>A​(p.Val417Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,613,940 control chromosomes in the GnomAD database, including 32,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V417A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2730 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29948 hom.)
• Consequence: ABCC2 NM_000392.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.327
• Publications: 359 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 (MetaRNN=0.00972563).
• BP6: Variant 10-99804058-G-A is Benign according to our data. Variant chr10-99804058-G-A is described in ClinVar as Benign. ClinVar VariationId is 255992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.1249G>A	p.Val417Ile	missense_variant	Exon 10 of 32	ENST00000647814.1	NP_000383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.1249G>A	p.Val417Ile	missense_variant	Exon 10 of 32		NM_000392.5	ENSP00000497274.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28258 AN: 152000 Hom.: 2734 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.191 AC: 47979 AN: 251224 AF XY: 0.197

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0875

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.200 AC: 292615 AN: 1461822 Hom.: 29948 Cov.: 34 AF XY: 0.203 AC XY: 147754 AN XY: 727206

African (AFR) AF: 0.187 AC: 6262 AN: 33476

American (AMR) AF: 0.153 AC: 6841 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5600 AN: 26136

East Asian (EAS) AF: 0.108 AC: 4279 AN: 39696

South Asian (SAS) AF: 0.277 AC: 23890 AN: 86256

European-Finnish (FIN) AF: 0.166 AC: 8884 AN: 53418

Middle Eastern (MID) AF: 0.265 AC: 1529 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 223982 AN: 1111962

Other (OTH) AF: 0.188 AC: 11348 AN: 60392

GnomAD4 genome AF: 0.186 AC: 28256 AN: 152118 Hom.: 2730 Cov.: 32 AF XY: 0.182 AC XY: 13569 AN XY: 74392

African (AFR) AF: 0.182 AC: 7548 AN: 41476

American (AMR) AF: 0.158 AC: 2409 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 713 AN: 3468

East Asian (EAS) AF: 0.0958 AC: 496 AN: 5176

South Asian (SAS) AF: 0.269 AC: 1293 AN: 4814

European-Finnish (FIN) AF: 0.159 AC: 1680 AN: 10596

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13544 AN: 68004

Other (OTH) AF: 0.193 AC: 407 AN: 2114

Alfa AF: 0.196 Hom.: 11368

Bravo AF: 0.186

TwinsUK AF: 0.210 AC: 779

ALSPAC AF: 0.203 AC: 781

ESP6500AA AF: 0.187 AC: 824

ESP6500EA AF: 0.195 AC: 1675

ExAC AF: 0.195 AC: 23702

Asia WGS AF: 0.161 AC: 562 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25087612, 22318656, 21691255, 15821043) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dubin-Johnson syndrome Benign:2

Mar 06, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 08, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCC2-related disorder Benign:1

Jan 16, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.023
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	.;T
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.24	N;N
PhyloP100		-0.33
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.63	.;N
REVEL	Benign	0.23
Sift	Benign	0.16	.;T
Sift4G	Benign	0.16	.;T
Polyphen		0.0080	B;B
Vest4		0.018
MPC		0.036
ClinPred		0.010	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.22
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2273697; hg19: chr10-101563815; COSMIC: COSV64984730;