10-99845793-G-C

Variant names:

• chr10-99845793-G-C
• rs17216282
• NM_000392.5:c.4146+11G>C

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.4146+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,606,394 control chromosomes in the GnomAD database, including 2,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (252 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2353 hom.)
• Consequence: ABCC2 NM_000392.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0310
• Publications: 12 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=-0.85).
• BP6: Variant 10-99845793-G-C is Benign according to our data. Variant chr10-99845793-G-C is described in ClinVar as [Benign]. Clinvar id is 298474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.4146+11G>C		intron_variant	Intron 29 of 31	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.3450+11G>C		intron_variant	Intron 24 of 26		XP_006717693.1
ABCC2	XR_945604.4	n.4292+11G>C		intron_variant	Intron 29 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.4146+11G>C		intron_variant	Intron 29 of 31		NM_000392.5	ENSP00000497274.1
ABCC2	ENST00000648523.1	n.33+11G>C		intron_variant	Intron 1 of 4			ENSP00000497778.1
ABCC2	ENST00000649459.1	n.494+11G>C		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0547 AC: 8298 AN: 151586 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0580

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.0198

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.0459 AC: 10949 AN: 238558 AF XY: 0.0464

Gnomad AFR exome AF: 0.0621

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.000734

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0626

GnomAD4 exome AF: 0.0531 AC: 77255 AN: 1454690 Hom.: 2353 Cov.: 32 AF XY: 0.0525 AC XY: 37927 AN XY: 722868

African (AFR) AF: 0.0630 AC: 2102 AN: 33356

American (AMR) AF: 0.0392 AC: 1709 AN: 43594

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3402 AN: 25880

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39610

South Asian (SAS) AF: 0.0187 AC: 1583 AN: 84868

European-Finnish (FIN) AF: 0.0232 AC: 1226 AN: 52948

Middle Eastern (MID) AF: 0.128 AC: 674 AN: 5280

European-Non Finnish (NFE) AF: 0.0567 AC: 62927 AN: 1109004

Other (OTH) AF: 0.0602 AC: 3620 AN: 60150

GnomAD4 genome AF: 0.0548 AC: 8319 AN: 151704 Hom.: 252 Cov.: 32 AF XY: 0.0532 AC XY: 3941 AN XY: 74090

African (AFR) AF: 0.0628 AC: 2596 AN: 41310

American (AMR) AF: 0.0580 AC: 881 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 422 AN: 3466

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5154

South Asian (SAS) AF: 0.0203 AC: 97 AN: 4784

European-Finnish (FIN) AF: 0.0227 AC: 239 AN: 10538

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0567 AC: 3852 AN: 67950

Other (OTH) AF: 0.0719 AC: 151 AN: 2100

Alfa AF: 0.0635 Hom.: 74

Bravo AF: 0.0594

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dubin-Johnson syndrome Benign:1

Jan 13, 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	-0.85
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		0.031
Mutation Taster		=100/0	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: rs17216282; hg19: chr10-101605550;