rs8187710

chr10-99851537-G-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.4544G>A(p.Cys1515Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,613,856 control chromosomes in the GnomAD database, including 3,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C1515C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.083 (719 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2827 hom.)
• Consequence: ABCC2 NM_000392.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.301

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=0.0022177398).
• BP6: Variant 10-99851537-G-A is Benign according to our data. Variant chr10-99851537-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 298481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99851537-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC2	NM_000392.5	c.4544G>A	p.Cys1515Tyr	missense_variant	32/32	ENST00000647814.1
ABCC2	XM_006717630.4	c.3848G>A	p.Cys1283Tyr	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC2	ENST00000647814.1	c.4544G>A	p.Cys1515Tyr	missense_variant	32/32		NM_000392.5	P1
ABCC2	ENST00000648523.1	c.*385G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.0825 AC: 12539 AN: 152076 Hom.: 709 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0572

Gnomad OTH AF: 0.0903

GnomAD3 exomes AF: 0.0528 AC: 13264 AN: 251416 Hom.: 576 AF XY: 0.0507 AC XY: 6891 AN XY: 135892

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0184

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0658

GnomAD4 exome AF: 0.0560 AC: 81918 AN: 1461662 Hom.: 2827 Cov.: 31 AF XY: 0.0549 AC XY: 39955 AN XY: 727138

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0188

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.0569

Gnomad4 OTH exome AF: 0.0673

GnomAD4 genome AF: 0.0826 AC: 12578 AN: 152194 Hom.: 719 Cov.: 33 AF XY: 0.0793 AC XY: 5899 AN XY: 74428

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.0703

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0572

Gnomad4 OTH AF: 0.0899

Alfa AF: 0.0644 Hom.: 1024

Bravo AF: 0.0916

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0558 AC: 215

ESP6500AA AF: 0.157 AC: 692

ESP6500EA AF: 0.0620 AC: 533

ExAC AF: 0.0524 AC: 6359

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0665

EpiControl AF: 0.0734

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, 22027652) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

ABCC2-related condition 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	0.043
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	2.3
Dann	Benign	0.58
DEOGEN2	Benign	0.062	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.045	N
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.48	N;N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.52	T
Polyphen		0.0	B;B
Vest4		0.018
MPC		0.052
ClinPred		0.0051	T
GERP RS		2.0
Varity_R		0.084
gMVP		0.41

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: rs8187710; hg19: chr10-101611294; COSMIC: COSV64985832;