rs17216282

Positions:

• chr10-99845793-G-C
• chr10-99845793-G-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.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

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=-0.85).
• 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/exons	MANE	UniProt
ABCC2	NM_000392.5	c.4146+11G>C		intron_variant		ENST00000647814.1
ABCC2	XM_006717630.4	c.3450+11G>C		intron_variant
ABCC2	XR_945604.4	n.4292+11G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC2	ENST00000647814.1	c.4146+11G>C		intron_variant			NM_000392.5	P1
ABCC2	ENST00000648523.1	c.34+11G>C		intron_variant, NMD_transcript_variant
ABCC2	ENST00000649459.1	n.494+11G>C		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.0459 AC: 10949 AN: 238558 Hom.: 374 AF XY: 0.0464 AC XY: 5953 AN XY: 128418

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 SAS exome AF: 0.0186

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

Gnomad4 AFR exome AF: 0.0630

Gnomad4 AMR exome AF: 0.0392

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.0232

Gnomad4 NFE exome AF: 0.0567

Gnomad4 OTH exome AF: 0.0602

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

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.0580

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.0227

Gnomad4 NFE AF: 0.0567

Gnomad4 OTH AF: 0.0719

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dubin-Johnson syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.85
CADD	Benign	11
DANN	Benign	0.60

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: rs17216282; hg19: chr10-101605550; COSMIC: COSV64985810;