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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000392.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	NM_000392.5	MANE Select	c.4146+11G>C		intron	N/A	NP_000383.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	ENST00000647814.1	MANE Select	c.4146+11G>C		intron	N/A	ENSP00000497274.1
	ABCC2	ENST00000648523.1		n.33+11G>C		intron	N/A	ENSP00000497778.1
	ABCC2	ENST00000649459.1		n.494+11G>C		intron	N/A

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Dubin-Johnson syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;