chr10-99834972-G-A

Variant names:

• chr10-99834972-G-A
• rs7476245
• NM_000392.5:c.3414+437G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000392.5(ABCC2):​c.3414+437G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 152,254 control chromosomes in the GnomAD database, including 827 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (827 hom., cov: 32)
• Consequence: ABCC2 NM_000392.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.997
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.3414+437G>A		intron_variant	Intron 24 of 31	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.2718+437G>A		intron_variant	Intron 19 of 26		XP_006717693.1
ABCC2	XM_047424598.1	c.3414+437G>A		intron_variant	Intron 24 of 25		XP_047280554.1
ABCC2	XR_945604.4	n.3619+437G>A		intron_variant	Intron 24 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.3414+437G>A		intron_variant	Intron 24 of 31		NM_000392.5	ENSP00000497274.1
ENSG00000295976	ENST00000734671.1	n.51-793C>T		intron_variant	Intron 1 of 1
ENSG00000295976	ENST00000734672.1	n.523-793C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13381 AN: 152136 Hom.: 830 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.0580

Gnomad FIN AF: 0.0379

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0861

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

GnomAD4 genome AF: 0.0879 AC: 13387 AN: 152254 Hom.: 827 Cov.: 32 AF XY: 0.0864 AC XY: 6435 AN XY: 74444

African (AFR) AF: 0.173 AC: 7197 AN: 41510

American (AMR) AF: 0.0740 AC: 1133 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3472

East Asian (EAS) AF: 0.0181 AC: 94 AN: 5188

South Asian (SAS) AF: 0.0579 AC: 279 AN: 4822

European-Finnish (FIN) AF: 0.0379 AC: 402 AN: 10614

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0572 AC: 3894 AN: 68024

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0708 Hom.: 621

Bravo AF: 0.0961

Asia WGS AF: 0.0370 AC: 130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.57
PhyloP100		-1.0
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: rs7476245; hg19: chr10-101594729;