rs72558202

Variant names:

• chr10-99845781-A-C
• rs72558202
• NM_000392.5:c.4145A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-99845781-A-C
• chr10-99845781-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000392.5(ABCC2):​c.4145A>C​(p.Gln1382Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1382R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ABCC2 NM_000392.5 missense, splice_region
• Scores: Splicing: ADA: 0.9938
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.24
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-99845781-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 8416.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.4145A>C	p.Gln1382Pro	missense_variant, splice_region_variant	Exon 29 of 32	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.3449A>C	p.Gln1150Pro	missense_variant, splice_region_variant	Exon 24 of 27		XP_006717693.1
ABCC2	XR_945604.4	n.4291A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 29 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.4145A>C	p.Gln1382Pro	missense_variant, splice_region_variant	Exon 29 of 32		NM_000392.5	ENSP00000497274.1
ABCC2	ENST00000648523.1	n.32A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 5			ENSP00000497778.1
ABCC2	ENST00000649459.1	n.493A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458674 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725240

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5498

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110938

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
PhyloP100		9.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.6	.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.98		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP		0.97
MPC		0.29
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.88
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72558202; hg19: chr10-101605538;