rs7080681

Variant names:

• chr10-99800412-G-A
• rs7080681
• NM_000392.5:c.1058G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000392.5(ABCC2):​c.1058G>A​(p.Arg353His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,614,130 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R353C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (47 hom.)
• Consequence: ABCC2 NM_000392.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.62
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019336939).
• BP6: Variant 10-99800412-G-A is Benign according to our data. Variant chr10-99800412-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 298446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2114/152268) while in subpopulation AFR AF = 0.0475 (1976/41560). AF 95% confidence interval is 0.0458. There are 43 homozygotes in GnomAd4. There are 976 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

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.1058G>A	p.Arg353His	missense	Exon 9 of 32	NP_000383.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	ENST00000647814.1	MANE Select	c.1058G>A	p.Arg353His	missense	Exon 9 of 32	ENSP00000497274.1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2103 AN: 152150 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00393 AC: 988 AN: 251120 AF XY: 0.00279

Gnomad AFR exome AF: 0.0497

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00163 AC: 2384 AN: 1461862 Hom.: 47 Cov.: 32 AF XY: 0.00138 AC XY: 1005 AN XY: 727226

African (AFR) AF: 0.0508 AC: 1700 AN: 33478

American (AMR) AF: 0.00349 AC: 156 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86256

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53414

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000197 AC: 219 AN: 1111996

Other (OTH) AF: 0.00432 AC: 261 AN: 60392

GnomAD4 genome AF: 0.0139 AC: 2114 AN: 152268 Hom.: 43 Cov.: 32 AF XY: 0.0131 AC XY: 976 AN XY: 74458

African (AFR) AF: 0.0475 AC: 1976 AN: 41560

American (AMR) AF: 0.00588 AC: 90 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68014

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00459 Hom.: 63

Bravo AF: 0.0164

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0513 AC: 226

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00491 AC: 596

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ABCC2-related disorder (1)
-	-	1	Dubin-Johnson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.068
DANN	Benign	0.92
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.6
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.19
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.020	B
Vest4		0.10
MVP		0.59
MPC		0.043
ClinPred		0.0070	T
GERP RS		-12
Varity_R		0.022
gMVP		0.081
Mutation Taster		=100/0	polymorphism

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: rs7080681; hg19: chr10-101560169; COSMIC: COSV64970703;