NM_000392.5:c.4508+170A>G

Variant names:

• chr10-99850966-A-G
• rs3740063
• NM_000392.5:c.4508+170A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000392.5(ABCC2):​c.4508+170A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,070 control chromosomes in the GnomAD database, including 13,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.41 (13260 hom., cov: 33)
• Consequence: ABCC2 NM_000392.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.994
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-99850966-A-G is Benign according to our data. Variant chr10-99850966-A-G is described in ClinVar as Benign. ClinVar VariationId is 1180976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.4508+170A>G		intron_variant	Intron 31 of 31	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.3812+170A>G		intron_variant	Intron 26 of 26		XP_006717693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.4508+170A>G		intron_variant	Intron 31 of 31		NM_000392.5	ENSP00000497274.1
ABCC2	ENST00000648523.1	n.*349+170A>G		intron_variant	Intron 4 of 4			ENSP00000497778.1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62767 AN: 151952 Hom.: 13253 Cov.: 33

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.437

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.413 AC: 62826 AN: 152070 Hom.: 13260 Cov.: 33 AF XY: 0.409 AC XY: 30396 AN XY: 74344

African (AFR) AF: 0.417 AC: 17275 AN: 41476

American (AMR) AF: 0.419 AC: 6406 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1656 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1205 AN: 5182

South Asian (SAS) AF: 0.344 AC: 1658 AN: 4824

European-Finnish (FIN) AF: 0.359 AC: 3791 AN: 10554

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.431 AC: 29264 AN: 67972

Other (OTH) AF: 0.436 AC: 921 AN: 2110

Alfa AF: 0.431 Hom.: 24546

Bravo AF: 0.418

Asia WGS AF: 0.298 AC: 1038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.86
CADD	Benign	0.43
DANN	Benign	0.24
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3740063; hg19: chr10-101610723;