10-99845936-A-G

Variant names:

• chr10-99845936-A-G
• rs3740065
• NM_000392.5:c.4146+154A>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.4146+154A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,192 control chromosomes in the GnomAD database, including 2,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (2029 hom., cov: 32)
• Consequence: ABCC2 NM_000392.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.675
• Publications: 53 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=-0.95).
• BP6: Variant 10-99845936-A-G is Benign according to our data. Variant chr10-99845936-A-G is described in ClinVar as Benign. ClinVar VariationId is 1181401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.32 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	NM_000392.5	MANE Select	c.4146+154A>G		intron	N/A	NP_000383.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	ENST00000647814.1	MANE Select	c.4146+154A>G		intron	N/A	ENSP00000497274.1
	ABCC2	ENST00000648523.1		n.33+154A>G		intron	N/A	ENSP00000497778.1
	ABCC2	ENST00000649459.1		n.494+154A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23022 AN: 152074 Hom.: 2007 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.144

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

GnomAD4 genome AF: 0.152 AC: 23089 AN: 152192 Hom.: 2029 Cov.: 32 AF XY: 0.154 AC XY: 11455 AN XY: 74392

African (AFR) AF: 0.215 AC: 8940 AN: 41518

American (AMR) AF: 0.135 AC: 2060 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3470

East Asian (EAS) AF: 0.333 AC: 1725 AN: 5180

South Asian (SAS) AF: 0.221 AC: 1065 AN: 4814

European-Finnish (FIN) AF: 0.101 AC: 1069 AN: 10592

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7183 AN: 68018

Other (OTH) AF: 0.150 AC: 317 AN: 2114

Alfa AF: 0.124 Hom.: 6024

Bravo AF: 0.159

Asia WGS AF: 0.297 AC: 1029 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.1
DANN	Benign	0.60
PhyloP100		-0.68
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: rs3740065; hg19: chr10-101605693;