rs17222723

chr10-99836239-T-A

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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:4
• Conservation: PhyloP100: -2.72

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC2	NM_000392.5	c.3563T>A	p.Val1188Glu	missense_variant	25/32	ENST00000647814.1
ABCC2	XM_006717630.4	c.2867T>A	p.Val956Glu	missense_variant	20/27
ABCC2	XM_047424598.1	c.3563T>A	p.Val1188Glu	missense_variant	25/26
ABCC2	XR_945604.4	n.3768T>A		non_coding_transcript_exon_variant	25/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC2	ENST00000647814.1	c.3563T>A	p.Val1188Glu	missense_variant	25/32		NM_000392.5	P1

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

GnomAD3 exomes AF: 0.0453 AC: 11386 AN: 251494 Hom.: 386 AF XY: 0.0457 AC XY: 6213 AN XY: 135920

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 SAS exome AF: 0.0182

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

Gnomad4 AFR exome AF: 0.0607

Gnomad4 AMR exome AF: 0.0390

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.0232

Gnomad4 NFE exome AF: 0.0569

Gnomad4 OTH exome AF: 0.0602

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

Gnomad4 AFR AF: 0.0599

Gnomad4 AMR AF: 0.0579

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0567

Gnomad4 OTH AF: 0.0707

Alfa AF: 0.0604 Hom.: 260

Bravo AF: 0.0586

TwinsUK AF: 0.0607 AC: 225

ALSPAC AF: 0.0555 AC: 214

ESP6500AA AF: 0.0595 AC: 262

ESP6500EA AF: 0.0617 AC: 531

ExAC AF: 0.0430 AC: 5221

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.0661

EpiControl AF: 0.0727

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 25087612, 18926681, 16628674) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

ABCC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

This variant is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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
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;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.087	N
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.52	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
Polyphen		0.0	B;B
Vest4		0.097
MPC		0.051
ClinPred		0.0029	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.089
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs17222723; hg19: chr10-101595996; COSMIC: COSV64985796;