rs717620

chr10-99782821-C-T

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.-24C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,610,598 control chromosomes in the GnomAD database, including 29,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2125 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27698 hom.)
• Consequence: ABCC2 NM_000392.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.07

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 (BayesDel_noAF=-0.78).
• BP6: Variant 10-99782821-C-T is Benign according to our data. Variant chr10-99782821-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 298437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC2	NM_000392.5	c.-24C>T		5_prime_UTR_variant	1/32	ENST00000647814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC2	ENST00000647814.1	c.-24C>T		5_prime_UTR_variant	1/32		NM_000392.5	P1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23555 AN: 152080 Hom.: 2127 Cov.: 33

Gnomad AFR AF: 0.0618

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.171 AC: 42814 AN: 251040 Hom.: 3942 AF XY: 0.171 AC XY: 23245 AN XY: 135676

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.213

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.190 AC: 276603 AN: 1458400 Hom.: 27698 Cov.: 31 AF XY: 0.188 AC XY: 136569 AN XY: 725676

Gnomad4 AFR exome AF: 0.0536

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.155 AC: 23547 AN: 152198 Hom.: 2125 Cov.: 33 AF XY: 0.156 AC XY: 11601 AN XY: 74402

Gnomad4 AFR AF: 0.0617

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.179

Alfa AF: 0.191 Hom.: 6167

Bravo AF: 0.147

Asia WGS AF: 0.154 AC: 533 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 18, 2017

- -

ABCC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2023

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

This variant is associated with the following publications: (PMID: 19415824, 22664480, 16788565, 24743544, 19890061, 21451505) -

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
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.49

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: rs717620; hg19: chr10-101542578; COSMIC: COSV64970575;