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GeneBe

rs2273697

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/19 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

Scores

13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.327
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 255992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99804058-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABCC2NM_000392.5 linkuse as main transcriptc.1249G>A p.Val417Ile missense_variant 10/32 ENST00000647814.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCC2ENST00000647814.1 linkuse as main transcriptc.1249G>A p.Val417Ile missense_variant 10/32 NM_000392.5 P1

Frequencies

GnomAD3 genomes
AF:
0.186
AC:
28258
AN:
152000
Hom.:
2734
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.191
AC:
47979
AN:
251224
Hom.:
4877
AF XY:
0.197
AC XY:
26739
AN XY:
135788
show subpopulations
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 SAS exome
AF:
0.278
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
show subpopulations
Gnomad4 AFR exome
AF:
0.187
Gnomad4 AMR exome
AF:
0.153
Gnomad4 ASJ exome
AF:
0.214
Gnomad4 EAS exome
AF:
0.108
Gnomad4 SAS exome
AF:
0.277
Gnomad4 FIN exome
AF:
0.166
Gnomad4 NFE exome
AF:
0.201
Gnomad4 OTH exome
AF:
0.188
GnomAD4 genome
AF:
0.186
AC:
28256
AN:
152118
Hom.:
2730
Cov.:
32
AF XY:
0.182
AC XY:
13569
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.182
Gnomad4 AMR
AF:
0.158
Gnomad4 ASJ
AF:
0.206
Gnomad4 EAS
AF:
0.0958
Gnomad4 SAS
AF:
0.269
Gnomad4 FIN
AF:
0.159
Gnomad4 NFE
AF:
0.199
Gnomad4 OTH
AF:
0.193
Alfa
AF:
0.199
Hom.:
8081
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

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018This variant is associated with the following publications: (PMID: 25087612, 22318656, 21691255, 15821043) -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Dubin-Johnson syndrome Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 08, 2018- -
ABCC2-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 16, 2023This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.13
N
MetaRNN
Benign
0.0097
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.24
N;N
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.19
T
Polyphen
0.0080
B;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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2273697; hg19: chr10-101563815; COSMIC: COSV64984730; API