rs17222723

Variant names:

• chr10-99836239-T-A
• rs17222723
• NM_000392.5:c.3563T>A
• ABCC2 p.Val1188Glu

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.3563T>A​(p.Val1188Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0532 in 1,613,986 control chromosomes in the GnomAD database, including 2,596 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.054 (249 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2347 hom.)
• Consequence: ABCC2 NM_000392.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.72
• Publications: 101 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)

ENSG00000295976 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002881676).
• BP6: Variant 10-99836239-T-A is Benign according to our data. Variant chr10-99836239-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 298467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.058 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.3563T>A	p.Val1188Glu	missense	Exon 25 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.3563T>A	p.Val1188Glu	missense	Exon 25 of 32	ENSP00000497274.1	Q92887
	ENSG00000295976	ENST00000734671.1		n.51-2060A>T		intron	N/A
	ENSG00000295976	ENST00000734672.1		n.523-2060A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 8202 AN: 152062 Hom.: 245 Cov.: 32

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0709

GnomAD2 exomes AF: 0.0453 AC: 11386 AN: 251494 AF XY: 0.0457

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.0360

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0568

Gnomad OTH exome AF: 0.0611

GnomAD4 exome AF: 0.0531 AC: 77680 AN: 1461806 Hom.: 2347 Cov.: 32 AF XY: 0.0525 AC XY: 38200 AN XY: 727210

African (AFR) AF: 0.0607 AC: 2032 AN: 33478

American (AMR) AF: 0.0390 AC: 1746 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3426 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0186 AC: 1603 AN: 86248

European-Finnish (FIN) AF: 0.0232 AC: 1238 AN: 53416

Middle Eastern (MID) AF: 0.129 AC: 744 AN: 5766

European-Non Finnish (NFE) AF: 0.0569 AC: 63242 AN: 1111948

Other (OTH) AF: 0.0602 AC: 3636 AN: 60390

GnomAD4 genome AF: 0.0540 AC: 8223 AN: 152180 Hom.: 249 Cov.: 32 AF XY: 0.0523 AC XY: 3891 AN XY: 74402

African (AFR) AF: 0.0599 AC: 2487 AN: 41508

American (AMR) AF: 0.0579 AC: 885 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 423 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4818

European-Finnish (FIN) AF: 0.0225 AC: 238 AN: 10600

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0567 AC: 3858 AN: 67996

Other (OTH) AF: 0.0707 AC: 149 AN: 2108

Alfa AF: 0.0604 Hom.: 260

Bravo AF: 0.0586

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.0661

EpiControl AF: 0.0727

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	ABCC2-related disorder (1)
-	-	1	Dubin-Johnson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.0030
DANN	Benign	0.17
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.52	N
PhyloP100		-2.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.21
Sift	Benign	0.97	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.089
gMVP		0.28
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17222723;

hg19: chr10-101595996;

COSMIC: COSV64985796;