rs3740067

Variant names:

• chr10-99844024-C-G
• rs3740067
• NM_000392.5:c.3843+124C>G

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.3843+124C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 913,174 control chromosomes in the GnomAD database, including 55,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7705 hom., cov: 32)
  • Exomes 𝑓: 0.35 (47464 hom.)
• Consequence: ABCC2 NM_000392.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.585
• Publications: 8 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)

ENSG00000295976 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-99844024-C-G is Benign according to our data. Variant chr10-99844024-C-G is described in ClinVar as Benign. ClinVar VariationId is 1275707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.3843+124C>G		intron_variant	Intron 27 of 31	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.3147+124C>G		intron_variant	Intron 22 of 26		XP_006717693.1
ABCC2	XR_945604.4	n.4048+124C>G		intron_variant	Intron 27 of 29
ABCC2	XM_047424598.1	c.*210C>G		downstream_gene_variant			XP_047280554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.3843+124C>G		intron_variant	Intron 27 of 31		NM_000392.5	ENSP00000497274.1
ABCC2	ENST00000649459.1	n.191+124C>G		intron_variant	Intron 1 of 4
ENSG00000295976	ENST00000734671.1	n.50+637G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46486 AN: 151976 Hom.: 7710 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.332

GnomAD4 exome AF: 0.350 AC: 266338 AN: 761078 Hom.: 47464 AF XY: 0.350 AC XY: 141379 AN XY: 403498

African (AFR) AF: 0.183 AC: 3561 AN: 19496

American (AMR) AF: 0.348 AC: 13479 AN: 38696

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 7373 AN: 21174

East Asian (EAS) AF: 0.234 AC: 8469 AN: 36256

South Asian (SAS) AF: 0.327 AC: 22774 AN: 69604

European-Finnish (FIN) AF: 0.343 AC: 16690 AN: 48634

Middle Eastern (MID) AF: 0.331 AC: 973 AN: 2944

European-Non Finnish (NFE) AF: 0.370 AC: 180206 AN: 487036

Other (OTH) AF: 0.344 AC: 12813 AN: 37238

GnomAD4 genome AF: 0.306 AC: 46498 AN: 152096 Hom.: 7705 Cov.: 32 AF XY: 0.306 AC XY: 22715 AN XY: 74330

African (AFR) AF: 0.185 AC: 7696 AN: 41504

American (AMR) AF: 0.337 AC: 5152 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1220 AN: 3472

East Asian (EAS) AF: 0.232 AC: 1204 AN: 5180

South Asian (SAS) AF: 0.322 AC: 1552 AN: 4814

European-Finnish (FIN) AF: 0.334 AC: 3525 AN: 10542

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24881 AN: 67980

Other (OTH) AF: 0.333 AC: 704 AN: 2112

Alfa AF: 0.338 Hom.: 1321

Bravo AF: 0.300

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.56
PhyloP100		-0.58
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: rs3740067; hg19: chr10-101603781; COSMIC: COSV64988729;