chr10-99782821-C-T

Variant names:

• chr10-99782821-C-T
• rs717620
• NM_000392.5:c.-24C>T

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.-24C>T variant causes a 5 prime UTR premature start codon gain 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2125 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27698 hom.)
• Consequence: ABCC2 NM_000392.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.07
• Publications: 440 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 (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 Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.-24C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 32	ENST00000647814.1	NP_000383.2
ABCC2	NM_000392.5	c.-24C>T		5_prime_UTR_variant	Exon 1 of 32	ENST00000647814.1	NP_000383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.-24C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 32		NM_000392.5	ENSP00000497274.1
ABCC2	ENST00000647814.1	c.-24C>T		5_prime_UTR_variant	Exon 1 of 32		NM_000392.5	ENSP00000497274.1

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

GnomAD2 exomes AF: 0.171 AC: 42814 AN: 251040 AF XY: 0.171

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 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

African (AFR) AF: 0.0536 AC: 1794 AN: 33462

American (AMR) AF: 0.132 AC: 5906 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 5243 AN: 26108

East Asian (EAS) AF: 0.205 AC: 8120 AN: 39654

South Asian (SAS) AF: 0.112 AC: 9671 AN: 86192

European-Finnish (FIN) AF: 0.194 AC: 10346 AN: 53312

Middle Eastern (MID) AF: 0.132 AC: 760 AN: 5764

European-Non Finnish (NFE) AF: 0.202 AC: 223758 AN: 1108902

Other (OTH) AF: 0.183 AC: 11005 AN: 60296

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

African (AFR) AF: 0.0617 AC: 2562 AN: 41556

American (AMR) AF: 0.163 AC: 2494 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 730 AN: 3466

East Asian (EAS) AF: 0.206 AC: 1069 AN: 5180

South Asian (SAS) AF: 0.117 AC: 563 AN: 4830

European-Finnish (FIN) AF: 0.190 AC: 2009 AN: 10590

Middle Eastern (MID) AF: 0.142 AC: 41 AN: 288

European-Non Finnish (NFE) AF: 0.199 AC: 13495 AN: 67984

Other (OTH) AF: 0.179 AC: 377 AN: 2106

Alfa AF: 0.183 Hom.: 11582

Bravo AF: 0.147

Asia WGS AF: 0.154 AC: 533 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jul 18, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCC2-related disorder Benign:1

Jul 22, 2024

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).

Dubin-Johnson syndrome Benign:1

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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.49
PhyloP100		1.1
PromoterAI		-0.038	Neutral
Mutation Taster		=298/2	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

Other links and lift over

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