NM_000392.5:c.1249G>A

Variant names:

• chr10-99804058-G-A
• rs2273697
• NM_000392.5:c.1249G>A

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.1249G>A​(p.Val417Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,613,940 control chromosomes in the GnomAD database, including 32,678 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V417A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2730 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29948 hom.)
• Consequence: ABCC2 NM_000392.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.327
• Publications: 359 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=0.00972563).
• BP6: Variant 10-99804058-G-A is Benign according to our data. Variant chr10-99804058-G-A is described in ClinVar as Benign. ClinVar VariationId is 255992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 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.1249G>A	p.Val417Ile	missense	Exon 10 of 32	NP_000383.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	ENST00000647814.1	MANE Select	c.1249G>A	p.Val417Ile	missense	Exon 10 of 32	ENSP00000497274.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28258 AN: 152000 Hom.: 2734 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.191 AC: 47979 AN: 251224 AF XY: 0.197

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0875

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.200 AC: 292615 AN: 1461822 Hom.: 29948 Cov.: 34 AF XY: 0.203 AC XY: 147754 AN XY: 727206

African (AFR) AF: 0.187 AC: 6262 AN: 33476

American (AMR) AF: 0.153 AC: 6841 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5600 AN: 26136

East Asian (EAS) AF: 0.108 AC: 4279 AN: 39696

South Asian (SAS) AF: 0.277 AC: 23890 AN: 86256

European-Finnish (FIN) AF: 0.166 AC: 8884 AN: 53418

Middle Eastern (MID) AF: 0.265 AC: 1529 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 223982 AN: 1111962

Other (OTH) AF: 0.188 AC: 11348 AN: 60392

GnomAD4 genome AF: 0.186 AC: 28256 AN: 152118 Hom.: 2730 Cov.: 32 AF XY: 0.182 AC XY: 13569 AN XY: 74392

African (AFR) AF: 0.182 AC: 7548 AN: 41476

American (AMR) AF: 0.158 AC: 2409 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 713 AN: 3468

East Asian (EAS) AF: 0.0958 AC: 496 AN: 5176

South Asian (SAS) AF: 0.269 AC: 1293 AN: 4814

European-Finnish (FIN) AF: 0.159 AC: 1680 AN: 10596

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13544 AN: 68004

Other (OTH) AF: 0.193 AC: 407 AN: 2114

Alfa AF: 0.196 Hom.: 11368

Bravo AF: 0.186

TwinsUK AF: 0.210 AC: 779

ALSPAC AF: 0.203 AC: 781

ESP6500AA AF: 0.187 AC: 824

ESP6500EA AF: 0.195 AC: 1675

ExAC AF: 0.195 AC: 23702

Asia WGS AF: 0.161 AC: 562 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.211

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Dubin-Johnson syndrome (2)
-	-	1	ABCC2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.023
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.24	N
PhyloP100		-0.33
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.23
Sift	Benign	0.16	T
Sift4G	Benign	0.16	T
Polyphen		0.0080	B
Vest4		0.018
MPC		0.036
ClinPred		0.010	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.22
Mutation Taster		=95/5	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: rs2273697; hg19: chr10-101563815; COSMIC: COSV64984730;